3.1.1 Histology

No histological feature is diagnostic of UC, but the combination of basal plasmacytosis, diffuse crypt atrophy and distortion, villous surface irregularity and mucus depletion are suggestive of a diagnosis of UC in the correct clinical context.14 Uneven distribution of inflammation within the colon or within biopsies can occur in patients with long-standing disease, or after treatment.

3.1.2 UC versus Crohn’s disease

In 5–15% of IBD patients, endoscopic and histological assessments cannot distinguish between Crohn’s colitis and UC, and these patients are labelled as IBD-unclassified (IBD-U), or if features are still indeterminate after colectomy histology is assessed, described as indeterminate colitis.15–17 IBD-U is more common in children than adults.18 In a small proportion of UC patients their diagnosis is later changed to IBD-U or Crohn’s disease.19–21

3.5.1 5-ASA dose

The ASCEND trials investigated the dose–response effect of 5-ASA (Asacol) for the induction of response in UC. ASCEND I randomised 301 patients with mild-moderately active UC to 2.4 g or 4.8 g of mesalazine.61 At week 6, a similar proportion of patients experienced improvement in either group (51% vs 56%, p=NS). When results were stratified according to disease severity, patients with moderate disease had better response to 4.8 g/day, but there was no significant difference in dose–response in those with mildly active disease. ASCEND II confirmed that patients with moderately active UC had a better response to 4.8 g/day than 2.4 g/day (72% vs 59%, p=0.036).62 In the ASCEND III trial, 772 patients with moderately active UC were randomised to receive 2.4 g/day or 4.8 g/day mesalazine.63 Despite the large numbers in the study, there was no difference in the primary end-point of treatment success (complete clinical remission or partial response). There was a small but significant difference in remission, with 43% of patients on 4.8 g/day versus 35% of those on 2.4 g/day achieving remission at 6 weeks. Subgroup analysis showed that patients who had received steroid, oral 5-ASA and rectal therapies were more likely to respond to the higher dose.63 4.8 g/day 5-ASA is associated with more rapid symptom resolution than 2.4 g/day,64 and higher rates of mucosal healing at 3 and 6 weeks.65 Similarly, the 5-ASA MMX trials also showed that 4.8 g/day was more effective than 2.4 g/day in the subpopulation with prior exposure to 5-ASA, and in those who had an incomplete response to 8 weeks of 5-ASA MMX at 2.4 g/day.66

A post-hoc analysis of the ASCEND I and II data also showed that there was greater mucosal healing in the 4.8 g/day group compared with 2.4 g/day.65 There is also evidence of the effect of escalating doses of 5-ASA from the DEAR trial.67 In this study patients with quiescent UC but with a raised faecal calprotectin >50 µg/g had their current 5-ASA dose increased (from 1.2 g (or nil) to 2.4 g, or from 2.4 g to 4.8 g/day). Compared with a control group there was a significant increase in patients remaining in clinical remission, and with a faecal calprotectin <50 µg/g at 6 weeks. Oral 5-ASA is no more effective than oral sulphasalazine,59 but may be better tolerated (RR for an adverse event 0.48, 95% CI 0.36 to 0.63).57

Following commencement of 5-ASA, 10–30% of patients are in symptomatic remission at week 2, 30–45% by week 4 and 35–50% by week 8.68–71 High-dose 5-ASA should not be used routinely, but patients with symptoms that are failing to settle should have their dose increased.

3.5.2 Oral and enema 5-ASA

All UC patients (including those with extensive disease) should be offered a combination of oral and enema 5-ASA, and those with incomplete response to oral 5-ASA should have topical therapy added. The combination of oral and topical 5-ASA therapy is superior to monotherapy even in patients with pancolitis.72 73 A meta-analysis of four studies in active UC confirmed a relative risk of no remission of 0.65 (95% CI 0.47 to 0.91) for combined oral and topical therapy over oral 5-ASA alone for induction of remission.74 A small study in 18 UC patients with frequent relapses on standard dose oral 5-ASA showed the benefits of high-dose 5-ASA combined with 5-ASA enemas.75 Despite the evident benefits of enema therapy, the practical difficulty patients have in administering and retaining enemas remains a major obstacle, and support and education in this area is much needed.

3.5.3 Nephrotoxicity

5-ASA therapy may be associated with renal complications.76 77 It is important to obtain baseline renal function, as renal disease may also be a primary complication of IBD itself. Renal manifestations of IBD include nephrolithiasis, urinary obstruction, fistulisation, glomerular disease, protein-losing nephropathy, secondary amyloidosis and renal failure.76 78 Nephrotic syndrome due to minimal-change nephropathy has been reported in a patient taking sulfasalazine, resolving with drug withdrawal and high-dose oral corticosteroids.79 Allergic reactions to sulfasalazine have recurred on challenge 5-ASA.80 Tubulointerstitial nephritis is a rare idiosyncratic reaction to 5-ASA therapy.

A UK study evaluated 151 patients with renal impairment associated with 5-ASA use.81 The temporal association with the drug, improvement on 5-ASA withdrawal (in 30% of the cases) and the recurrent renal damage on re-challenge in five patients was consistent with a true relationship, and a suggestive genetic association in the HLA region (p=1×10^–7) was identified. Permanent renal replacement therapy was required in 15 patients. The median time on 5-ASA before renal impairment was 3 years (95% CI 2.3 to 3.7), and regular monitoring of renal function was uncommon. The frequency of 5-ASA nephrotoxicity has been estimated at 1 in 4000 patient years.82 83 Given the unpredictable nature of this occurrence, it is suggested that patients on long-term 5-ASA therapy should have renal function checked, including eGFR before starting, after 2–3 months, and then annually long-term, although there are no data to support a particular surveillance interval. Those with impaired renal function should be monitored more closely.

3.6.1 Budesonide MMX

Randomised controlled trials have shown that oral budesonide MMX 9 mg daily is significantly more effective than placebo and can induce remission in mild to moderate UC, being as effective as 5-ASA.86–88 The CORE I and CORE II studies compared oral budesonide MMX 9 mg/day and 6 mg/day with placebo in patients with mild to moderate left-sided and extensive UC.87 Additional control groups were included (Asacol 2.4 g/day (CORE I) and Entocort EC 9 mg (CORE II)), but the studies were not powered to demonstrate differences between budesonide MMX and these controls. In a pooled analysis of both trials, the week 8 combined clinical and endoscopic remission rates were 17.7% for budesonide MMX 9 mg versus 6.2% for placebo (p=0.0002). A Cochrane systematic review concluded that the quality of evidence was moderate, and benefit was not demonstrated clearly for extensive UC but was significant for those with left-sided disease.89 Endoscopic healing rates were 27.6% versus 17.1% (p=0.009) for budesonide MMX and placebo, respectively.90 The 6 mg dose was not significantly better than placebo. Another placebo-controlled trial of budesonide MMX in mild to moderately active UC showed significant benefit in clinical, endoscopic and histological remission.91 Although no adequately powered comparative trials between budesonide MMX and conventional corticosteroids have been conducted to date, budesonide MMX may be considered as an alternative to conventional corticosteroids in patients with mild-moderate UC and failure of response to 5-ASA therapy.92

Budesonide has a lower rate of systemic adverse effects than conventional corticosteroids (33% vs 55%), and is not associated with adrenal suppression or a significant reduction in bone mineral density.93 94 Ileal-release budesonide does not induce remission in mild-moderately active UC and was in fact inferior to placebo and 5-ASA in two studies and a systematic review.89 93 95

3.6.2 Beclomethasone dipropionate

Oral beclomethasone dipropionate is a second-generation corticosteroid and may also be an alternative to conventional corticosteroids. In a randomised controlled trial in 282 patients, oral beclomethasone dipropionate 5 mg daily for 4 weeks, then alternate weekly for a further 4 weeks was shown to be non-inferior to prednisolone in efficacy, but there was also no difference in the co-primary end-point of steroid-related adverse events and reduction in morning cortisol below 150 nmol/L.96 In patients with active left-sided or extensive UC, oral beclomethasone dipropionate 5 mg/day has been demonstrated as equivalent to 2.4 g 5-ASA,97 and has been shown as more effective when added to 5-ASA compared with 5-ASA alone.98

Although more expensive, topically-acting oral corticosteroids are an alternative to prednisolone in UC patients with mild to moderate disease and 5-ASA failure.

3.7.1 Failure of oral corticosteroids

There is variation in the definition of severe ulcerative colitis. The Mayo score or Disease Activity Index32 does not include systemic symptoms (fever, anaemia or abnormal inflammatory markers), whereas the Truelove and Witts criteria for severe disease102 specify one or more of these. Patients with systemic symptoms of fever, severe pain, significant anaemia, or those who are generally unwell and not tolerating their symptoms should be admitted for inpatient management (see Section 3.12:on Acute severe ulcerative colitis). Prolonging treatment with high-dose oral corticosteroids has a diminishing chance of achieving remission, and of those who do respond, there will be many who become corticosteroid-dependent (22% at 1 year in a study from the pre-biologic era103). There is however increasing risk of infective, metabolic and surgical complications for deteriorating patients who may require emergency admission and colectomy.104 105 There is no evidence from a meta-regression analysis that doses above 60 mg of methylprednisolone reduce colectomy rates in severe UC.106 Although there are few data on the time-course of response to oral corticosteroids, a study comparing oral prednisolone with prednisolone metasulphobenzoate showed that improvements in clinical and endoscopic disease activity may be seen within 2 weeks of treatment with oral prednisolone 40 mg/day,107 so patients not responding after 2 weeks should be considered for treatment escalation to biologics or admission to hospital, depending on how systemically unwell they are.

3.9.1 Thiopurines

While studies vary in quality, meta-analyses consistently report a benefit of thiopurines over placebo for the maintenance of steroid-induced remission in UC but not for induction of remission. Meta-analysis of three randomised controlled thiopurine maintenance studies favours thiopurines over placebo (RR 0.6, 95% CI 0.37 to 0.95).118 In a further meta-analysis, OR was 2.59 (95% CI 1.26 to 5.3), absolute risk reduction was 23% and the number-needed-to-treat (NNT) to prevent one recurrence was five.119 A recent Cochrane review included 232 patients from four maintenance studies of azathioprine versus placebo and showed a benefit of azathioprine over placebo (44% vs 65% failure, respectively, RR 0.68, 95% CI 0.54 to 0.86).120 The side effects of thiopurines, both short- and long-term, should be considered (see Section 5.2.2on Drug management: thiopurines) in choice of therapy, and also in decisions about duration of therapy, particularly in older patients (see Section 5.2.7.1 Stopping thiopurines).

3.9.2 Infliximab

In the ACT1 and ACT2 clinical trials, UC patients with active disease despite corticosteroids and/or thiopurines (and/or 5-ASA for ACT2 only) were treated with 5 or 10 mg/kg infliximab or placebo at weeks 0, 2 and 6, and followed to week 54 (ACT1) or week 30 (ACT2). Clinical response at week 8 was similar in both active doses, and pooled data from both trials were 67% for 5 mg/kg versus 33% for placebo.121 At week 30 combined clinical remission rates were 30% for 5 mg/kg (13% for placebo), with very similar remission rates sustained to week 54 in ACT1. Corticosteroid-free remission rates were 22% for 5 mg/kg at week 30, sustained to week 54 in ACT1. In the UC SUCCESS study, patients in whom corticosteroid therapy had failed and who were receiving infliximab and azathioprine combination therapy (40%) had significantly higher remission rates at week 16, compared with infliximab alone (22%).122 10% of these patients had previously received immunomodulators, but not anti-TNF therapy. Cohort studies also show benefit of using infliximab for patients with corticosteroid-dependent UC, with steroid-free remission rates of 47% at 1 year, 77% colectomy-free at median 41.5 months, and better outcomes for those on combination therapy with thiopurines, and also in those who were thiopurine-naïve initially.123 124 Real-life experience of infliximab treatment in UC patients where conventional therapy had failed showed primary response rates vary from 67% (in a study from Leuven, starting infliximab prior to 2006 and including patients recruited to the ACT1 study),125 to 78% in a French multicentre study of patients treated from 2000 to 2009.126

3.9.3 Adalimumab

The ULTRA1 and ULTRA2 clinical trials127 128 showed that adalimumab 160 mg at week 0, 80 mg at week 2, followed by 40 mg fortnightly achieved remission at week 8 in 19% (placebo 9%) in ULTRA1 and 21% (placebo 11%) in the ULTRA2 study in patients naïve to anti-TNF therapy. The ULTRA2 maintenance study showed clinical remission rates at week 52 of 22% (12% placebo) in the anti-TNF naïve subgroup. Corticosteroid-free remission at week 52 in the same subgroup was 14% (placebo 6%). In the open-label extension study (ULTRA3), 25% remained in clinical remission on fortnightly or weekly adalimumab at 4 years after initial enrolment.129 Real-world data from the USA on the use of infliximab and adalimumab in UC patients naïve to anti-TNF therapy suggests comparable efficacy in the treatment of moderate to severe disease.130 131

3.9.4 Golimumab

The PURSUIT SC trial was an induction trial of golimumab, which included a dose-finding phase.132 1064 patients with UC that had failed to respond to either 5-ASA, oral corticosteroids, azathioprine or mercaptopurine, or who were steroid-dependent, were enrolled. All patients were anti-TNF naïve. 42.8% were receiving steroids at baseline, and a third were on thiopurines. Clinical response was achieved at week 6 in 51.0% on 200 mg/100 mg, 54.9% at 400 mg/200 mg, both significantly better (p<0.0001) versus placebo response rate of 30.3%. Clinical remission at week 6 was 17.8% (200 mg/100 mg), 17.9% 400 mg/200 mg, p<0.0001 versus placebo (6.4%). Both clinical response and remission at week 6, correlated with drug levels. Real-world observational studies corroborate with PURSUIT study observations.133

Network meta-analyses comparing the different anti-TNF agents in UC present conflicting data on the relative efficacy of infliximab, adalimumab and golimumab.134–137

3.9.5 Vedolizumab

In the GEMINI I clinical trial of vedolizumab in active UC, patients were enrolled to a randomised cohort. 225 patients received intravenous vedolizumab 300 mg at day 1 and 15, 149 patients received placebo and 521 patients were randomised to open-label vedolizumab in order to fulfil sample size requirements for the continuation maintenance study.138 139 Of the anti-TNF naïve patients in the randomised induction phase, clinical response at 6 weeks was seen in 26.3% of 76 patients on placebo versus 53.1% of 130 patients on vedolizumab, an estimated 26.4% difference (95% CI 12.4% to 40.4%). Clinical remission at 6 weeks was seen in 6.6% on placebo and 23.1% on vedolizumab, an estimated difference of 15.5% (95% CI 5.1% to 25.9%). Of the randomised responders who entered the maintenance phase (including those from the open-label induction cohort) and who had been anti-TNF naïve at entry, the durable clinical response rate (response at both weeks 6 and 52) was 26.6% for the 79 patients on placebo compared with 60.7% for the 145 patients given vedolizumab (either 4-weekly or 8-weekly). The estimated difference from placebo was 34.3% (95% CI 20.7% to 47.8%). The clinical remission rate at week 52 for the placebo group was 19.0%, and 46.9% for the combined vedolizumab group, an estimated difference from placebo of 28.0% (95% CI 14.9% to 41.1%). There were no clinically important differences in safety between the vedolizumab and placebo groups during the maintenance study.139

A recently published retrospective study from the VICTORY consortium analysed safety and efficacy data from 321 UC patients receiving vedolizumab therapy (71% of whom had previously been treated with anti-TNF therapy).140 Primary effectiveness outcomes were cumulative rates of clinical remission (defined as resolution of all UC-related symptoms on physician’s global assessment), endoscopic remission (defined as a Mayo endoscopic subscore of 0), corticosteroid-free remission and deep remission (clinical remission and endoscopic remission). In recognition of potential attrition bias, variability in follow-up and impact of right censoring, imputation analyses calculated 12 month rates as 20%, 17%, 15% and 14% respectively. On multivariable analyses, prior exposure to anti-TNF therapy was associated with a reduced probability of achieving clinical remission (HR 0.53, 95% CI 0.38 to 0.75) and endoscopic remission (HR 0.51, 95% CI 0.29 to 0.88).

Until recently there has been limited reporting of vedolizumab therapy outcomes for anti-TNF naïve patients with UC. However, a multicentre European retrospective study of 184 patients (50 Crohn’s disease and 134 UC patients) showed a greater efficacy than that reported in anti-TNF experienced patients with response, clinical remission and steroid-free remission rates at week 14 of 79.1%, 39.5% and 36.6%, respectively, in UC.141 The VARSITY trial has now been reported in abstract form and is the first head-to-head comparison of two biologic agents in IBD.142 Seven hundred and sixty-nine patients with moderately to severely active UC who had failed conventional therapies were randomised to intravenous vedolizumab 300 mg at weeks 0, 2 and 6 and then every 8 weeks, versus adalimumab subcutaneously 160 mg at week 0, 80 mg at week 2, and then 40 mg fortnightly, in a double-blind, double-dummy trial. Dose escalation was not permitted for either group. Recruitment of patients with previous anti-TNF therapy use was capped at 25% of the trial population. At 52 weeks, the primary end-point of clinical remission (a complete Mayo score ≤2 with no subscore >1) was achieved in 31.3% on vedolizumab versus 22.5% on adalimumab (p=0.006). Mucosal healing (Mayo endoscopic subscore ≤1) was 39.7% and 27.7%, respectively (p=0.0005). Corticosteroid-free remission rates (in those on steroids at baseline) at week 52 were not significantly different between the vedolizumab and adalimumab groups. Although no similar data are available for comparison with infliximab, these data provide support for vedolizumab as a first-line biologic option for UC failing conventional therapy.

3.9.6 Tofacitinib

A phase 2 dose-ranging induction study of the Janus kinase (JAK) inhibitor tofacitinib in patients with endoscopically confirmed active UC showed increased rates of clinical and endoscopic response and remission after 8 weeks of treatment that reached statistical significance for patients in the higher dosing arms of 10 mg and 15 mg oral twice daily.143 The OCTAVE-1 and OCTAVE-2 phase 3 induction studies confirmed the efficacy of a dose of 10 mg twice daily as induction therapy for active colitis.144 In these studies, the primary end-point of remission was defined clinically and endoscopically at week 8 by a total Mayo score ≤2, with no individual subscore >1 and a rectal bleeding subscore of 0. This was achieved by 18.5% and 16.6% of patients on active treatment in OCTAVE-1 and OCTAVE-2 versus 8.2% and 3.6% of patients on placebo (p=0.007 and p<0.001, respectively). For patients who had not previously received anti-TNF therapy, remission at 8 weeks on placebo and tofacitinib was 12.5% and 23.7% respectively (difference 11.2%; 95% CI 2.6% to 17.9%). Clinical responders to induction therapy (where response was defined as a decrease from baseline in the total Mayo score of ≥3 points and >30% with a rectal bleeding score decrease of at least one or a rectal bleeding subscore of 0 or 1) were eligible for enrolment in the maintenance OCTAVE-SUSTAIN trial. Of patients randomised to tofacitinib pooled from both trials, 57.6% (521/905) had a clinical response at week 8. This included both anti-TNF naïve and anti-TNF exposed patients. They were randomised 1:1:1 to oral tofacitinib 5 mg twice daily, 10 mg twice daily or placebo. After 1 year, remission was achieved in 34.3% in the tofacitinib 5 mg group, 40.6% in the tofacitinib 10 mg group and 11.1% in the placebo group (p<0.001 for both treatment arms vs placebo).

In the OCTAVE open-label follow-on study, patients who responded to induction therapy with 10 mg twice daily, but were then randomised to placebo in the OCTAVE-SUSTAIN study and then relapsed, were retreated with 10 mg twice daily open-label.145 Of these, 75.8% responded at month 2 and 67.5% at 1 year, showing that retreatment is effective after a break in therapy. The OCTAVE open-label study also showed that patients receiving 5 mg twice daily in the OCTAVE-SUSTAIN study who relapsed and were then treated with 10 mg twice daily open-label had a response rate of 58.6% at month 2 and 68.8% at 1 year.146

Although total adverse events did not appear to differ significantly between treatment and placebo groups, there was an increased risk of infections seen in tofacitinib treated patients during both induction and maintenance phases. In particular, herpes zoster occurred more often on active treatment, a finding consistent with prior experience of use of tofacitinib in patients with rheumatoid arthritis and psoriasis.147 148 Zoster vaccination should be considered before starting therapy in those aged over 70 years and those over 50 years considered at particularly high risk (such as recurrent shingles). As a live vaccination it must not be given for 3 months after stopping biologics, and tofacitinib should not be started for 4 weeks after vaccination (see Section 5.2.1.3.2 Live vaccines). Recent data from an open-label study149 in rheumatoid arthritis patients (over 50 years with at least one cardiovascular risk factor), comparing tofacitinib 5 mg or 10 mg twice daily with TNF-inhibitor therapy, have shown a five-fold increase in pulmonary embolus for the group on 10 mg twice daily tofacitinib compared with TNF inhibitor therapy),150 and at present the European Medicines Agency safety committee advises that the high dose should not be used in patients at increased risk of pulmonary embolus (heart failure, malignancy, impending/recent surgery, inherited coagulation disorders, previous thromboembolism, combined contraceptive therapy or HRT).151 Further data are required on the risks for UC patients treated with JAK inhibitors.

No comparative data for tofacitinib with biologics are available, and NICE approval has been granted for the treatment of moderate to severely active UC where conventional treatments or biological agents have not been tolerated, or have failed.152 Tofacitinib has the advantages of oral administration and, as a small molecule, immunogenicity is not an issue. This has to be weighed against the side effect profiles and costs of different agents.

3.9.7 Ustekinumab

The UNIFI trial, recently presented in abstract form, investigated ustekinumab as induction and maintenance therapy in moderate to severely active UC in adults who had failed to respond or were intolerant to corticosteroids, immunomodulators, anti-TNF therapy (one or more) or vedolizumab.153 154 Patients were randomised 1:1:1 to receive a single IV dose of placebo, 130 mg ustekinumab, or approximately 6 mg/kg ustekinumab (weight-tiered dosing: patients weighing ≤55 kg received 260 mg; patients weighing >55 kg and ≤85 kg received 390 mg; and patients weighing >85 kg received 520 mg), as in the UNITI Crohn’s studies. At week 8, 961 patients were evaluated. The primary end-point was clinical remission at week 8 (defined as a Mayo score ≤2 points, with no individual subscore >1), and was achieved by 15.6% on 130 mg ustekinumab, 15.5% on the approximately 6 mg/kg dose and 5.3% on placebo (p<0.001).153 Endoscopic healing (defined as Mayo endoscopy subscore of 0 or 1) was 26.3%, 27% and 13.8% in the three groups, respectively (p<0.001). Clinical response (decrease from baseline Mayo score of ≥30% and ≥3 points, with either a decrease from baseline in the rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) was 51.3%, 61.8% and 31.3% in the three groups, respectively (p<0.001). Both active treatment groups had a significant improvement in IBDQ, mucosal healing (endoscopic healing as defined above), and histological healing (defined as 0–<5% neutrophils in epithelium, no crypt destruction and no erosions, ulcerations or granulations) was 20.3%, 18.4% and 8.9% respectively at week 8. There was no difference in adverse events compared with placebo, with no malignancies, opportunistic infections or TB reported. In the maintenance continuation study, 523 patients with clinical response at week 8 were re-randomised to placebo, 8-weekly or 12-weekly dosing, with week 44 remission rates of 24%, 38.4% and 43.8%, respectively (p=0.002 for 8-weekly and p<0.001 for 12-weekly vs placebo).154 Effects were seen in both anti-TNF naïve and anti-TNF refractory patients, but numerical benefits of 8-weekly dosing (compared with 12-weekly) were restricted to the anti-TNF refractory population. The safety profile was consistent with that observed in Crohn’s disease.

At the time of writing, ustekinumab does not have licensing or NICE approval for its use in UC. It should be noted that (unlike the UNITI studies in Crohn’s disease and the GEMINI studies of vedolizumab in UC) the UNIFI study permitted inclusion of patients with failure of two classes of biologic (TNF inhibitors and vedolizumab) and results should be interpreted accordingly.

3.9.8 Methotrexate

Methotrexate has no role in the maintenance of remission in UC. A Cochrane review in 2015 of methotrexate use in comparison to placebo, 5-ASA, sulfasalazine and mercaptopurine does not support its use in maintenance of remission in UC.155 In a European double-blind randomised trial, 111 patients were allocated to 25 mg/week parenteral methotrexate versus placebo alongside prednisolone for a flare of UC.156 Methotrexate was not superior to placebo (31.7% vs 19.6% remission, p=0.15) for the primary end-point of steroid-free remission at week 16 (Mayo score ≤2 with no item >1 and complete withdrawal of steroids and no use of another immunosuppressant (IS), anti-TNF therapy or colectomy). Clinical remission at week 16 (Mayo score ≤2 with no item >1) was, however, significantly higher on methotrexate (41.7% vs 23.5% p=0.04). The MERIT study treated 179 patients with active UC with open-label methotrexate 25 mg SC weekly, plus a tapering prednisolone course for 12 weeks. At 16 weeks there was a 51% response rate, and 84 patients were randomised to continue 25 mg methotrexate SC or placebo. There was no difference in outcome at week 48, with 27% of those on methotrexate and 30% on placebo maintaining steroid-free clinical remission with no need for additional therapies.157

3.9.9 Choice of immunosuppressive or biological therapy

Patients with chronic active UC failing 5-ASA therapy have in the past been offered thiopurine therapy. As the range of alternatives grows and costs of biologics fall, there is strong justification for moving directly to other immunosuppressive drugs with less toxicity that may be easier to manage. Thiopurines still have a role as combination therapy and to reduce immunogenicity, but the therapeutic pyramid is changing rapidly.

Until the VARSITY study comparing vedolizumab with adalimumab,142 there had been no head-to-head studies comparing anti-TNF drugs, vedolizumab, tofacitinib and ustekinumab. Indirect means of comparison are much weaker and, at best, hypothesis-generating. Network meta-analyses have compared vedolizumab with anti-TNF drugs and show broadly similar benefits.158–160 In contrast, the VARSITY trial shows a significant benefit for vedolizumab compared with adalimumab 40 mg every other week.142 Two network meta-analyses that include tofacitinib, one in abstract form, show comparable efficacy to anti-TNF agents and vedolizumab.161 162 The choice of which immunosuppressive agent to use depends on a number of factors (box 2). Patients may prefer to receive oral or subcutaneous therapy rather than intravenous therapy, although the latter may be preferred for patients where non-adherence may be an issue. Tofacitinib as an oral agent, with no concerns about immunogenicity, is an attractive choice, but with little real-world experience as yet. Gut-selective therapy may be considered safer because of concerns about risk of malignancy or infection; at present there is little long-term comparative safety data between vedolizumab and anti-TNF therapy to support this, although the long-term trial extension safety profile over 9 years from the GEMINI trials is very reassuring.163 The presence of significant extraintestinal manifestations may also be a consideration. Other practical issues are shown in box 2.

3.9.10 Therapeutic choice after anti-TNF failure

Infliximab and other anti-TNF drugs have been used in UC for many years, and it is therefore important to consider alternatives for patients failing these drugs and who need to switch ‘out of class’ (see Sections 5.2.4.5: Common Disease Considerations, Primary non-response to anti-TNF therapy and 5.2.4.6: Common Disease Considerations, Secondary loss of response to anti-TNF therapy). It is important to note that surgery should always be discussed as an option in patients failing a therapeutic agent, particularly as there is generally a reduction in response to each successive immunosuppressive or biologic drug.

3.10.1 5-ASA suppositories in proctitis

When treating mild to moderate proctitis, first-line therapy should be 5-ASA suppositories. These medications achieve much higher mucosal concentrations of the drug and work faster and better than oral 5-ASA monotherapy in disease which is confined to the rectum.167 Higher response rates are achieved if topical therapies are combined with oral 5-ASA,168 thus patients not responding fully to suppositories should have early addition of oral therapy. Suppositories are preferred to enemas for proctitis as they deliver the drug specifically to the rectum (enemas tend to pool higher up in the sigmoid) and are also better tolerated/retained, as shown in a study comparing 5-ASA suppositories with hydrocortisone foam enemas.169 Topical 5-ASA is more effective than topical corticosteroid.170 A Cochrane review did not show a dose–response relationship for rectal therapy (although this review assessed treatment of distal colitis, which included both proctitis and left-sided colitis up to the splenic flexure).171 A further review evaluating mucosal healing showed a dose–response relationship for oral but not rectal 5-ASA (again evaluating proctitis along with distal colitis).172 Divided doses are less convenient for patients. A study comparing 1 g 5-ASA suppository daily versus 500 mg three times daily showed more convenience and similar efficacy (except for mucosal healing) for the once daily dose,173 and a further study showed no difference between 1 g daily and 500 mg twice daily.174 Administering this dose at bedtime is practical for most patients, allowing the suppository to be retained for the longest possible time.171

3.10.2 Maintenance therapy for proctitis

Many patients respond promptly to 5-ASA suppositories, and if they have infrequent flares, are happy to start suppositories when they begin to flare and not take regular maintenance therapy. This is quite safe as the colorectal cancer risk in proctitis is similar to the general population. For many, however, regular preventive treatment is needed, and 5-ASA suppositories are the most effective maintenance therapy for proctitis.109 175 In long-term treatment, however, this needs to be weighed against the importance of adherence, and some patients may choose not to use long-term rectal therapy and prefer oral therapy. It is worth noting that alternate night or every third night suppositories do not appear to reduce the rate of maintenance of remission substantially.170

3.10.3 Corticosteroid suppositories in proctitis

Steroid suppositories are also effective in proctitis but not as effective as 5-ASA and so their use should be confined to those who either do not tolerate or do not respond to 5-ASA.171 176 Oral 5-ASA should be continued if possible. For those not responding to 5-ASA, the addition of a prednisolone 5 mg suppository in the morning while continuing 5-ASA suppositories at bedtime is worth trying. A novel budesonide suppository was studied in a four-group, prospective, double-blind, double-dummy randomised trial to treat UC proctitis with budesonide 2 mg, budesonide 4 mg, 5-ASA 1 g, or budesonide 2 mg plus 5-ASA 1 g.177 The 8-week study conducted in Germany, Russia and the UK assessed a primary end-point of resolution of clinical symptoms for three consecutive days (score of 0 for rectal bleeding and stool frequency on modified UCDAI). Budesonide 4 mg was more effective than 2 mg, but no different from 5-ASA 1 g or the combination of budesonide 2 mg and 5-ASA 1 g.

3.10.4 Treatment options in refractory proctitis

A proctitis management flowchart is shown in figure 1. In severe or refractory proctitis, it is important to ensure that conventional therapy has been delivered appropriately (with assessment of adherence) and that the diagnosis is correct. Proximal constipation is common and may contribute to symptoms and poor response to therapy, as may co-existing irritable bowel syndrome. It is important to exclude other conditions that may be causing symptoms, including infection (lymphogranuloma venereum, Neisseria gonorrhoeae, herpes simplex virus, syphilis, Giardia duodenalis, amoebiasis), solitary rectal ulcer, psoriatic colitis, chemical colitis and rectal prolapse.178

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Figure 1

Management of proctitis.

If the diagnosis is correct and standard therapy has failed, then thiopurine therapy should be added,179 with escalation to biologics if no response.180–182 Many UC trials have excluded proctitis, but a case series of infliximab therapy for proctitis confirms good response.183 Patients with refractory proctitis have disabling symptoms but are often systemically well and are usually very reluctant to have proctocolectomy, so many other therapies have been assessed. There are many other treatments based on small trials or case series—for example, rectal tacrolimus (0.5 mg/mL, dose 3 mL twice daily)—although active absorption results in significant serum levels and close monitoring and dose adjustment are required to avoid toxicity.184

3.12.1 Corticosteroid therapy for ASUC

Intravenous corticosteroids such as hydrocortisone 100 mg four times daily or methylprednisolone 60 mg every 24 hours are the cornerstone of treatment of ASUC.106 203–205 Methylprednisolone has less mineralocorticoid effect than hydrocortisone at these doses and so causes significantly less hypokalaemia.206 There is no real advantage from giving higher doses and a bolus injection is as effective as a continuous infusion.207 Although a meta-regression analysis failed to show a relationship between dose and colectomy rate above the equivalent of 60 mg methylprednisolone,106 400 mg hydrocortisone is equivalent to 80 mg methylprednisolone. In children and adolescents, a dose of 1–1.5 mg/kg/day up to a maximum of 60 mg is recommended.208

In the landmark study by Truelove and Witts,102 oral cortisone 100 mg daily was given to 213 patients with acute flares of varying severity. Clinical remission was achieved in 41% of steroid treated patients versus 16% on placebo. In a subsequent study, 49 patients with severe UC were treated with intravenous prednisolone 21-phosphate and a clinical remission rate of 73% was noted 5 days after treatment.209 Definitions and terms differed widely in these studies compared with outcome measures in use today. A systematic review of 32 trials of steroid therapy for ASUC involving 1991 patients reported an overall response to steroids of 67%, with 29% (95% CI 28% to 31%) having colectomy. Mortality was 1% (n=22/1991; 95% CI 0.7% to 1.6%) and none of these outcomes changed between 1974 and 2006 (R²=0.07, p=0.8).106 In the CONSTRUCT cohort, after excluding those with infections or alternative diagnoses, response rate to intravenous steroids was 49%.200 Extending therapy beyond 7–10 days carries no additional benefit and increases toxicity.104 105 Patients should be assessed for a clinical and biochemical response after 3 days of intravenous steroid therapy to determine the need for salvage medical or surgical therapy.106 210

Risk of venous thromboembolism (VTE) is 2–3 fold higher compared with inpatients without IBD, so prophylactic subcutaneous low molecular weight heparin is important204 211 212 and does not precipitate or exacerbate colonic bleeding.213

ASUC patients should have stool culture and Clostridium difficile toxin assay.214 215  C. difficile infection has been associated with a worse outcome in hospitalised IBD patients.216–218 If C. difficile is detected (or strongly suspected), treatment with corticosteroids should not be withheld, but additional treatment with oral vancomycin given219 (see Section 5.1.3: Common Disease Considerations, Clostridium difficile infection associated with IBD). Amoebiasis should be considered in those with recent travel to endemic areas, in whom consideration should be given to addition of metronidazole pending stool microscopy and culture.

3.12.2 Predictors of outcomes of ASUC

Most studies of factors predicting colectomy in ASUC look at patients treated with intravenous steroids±salvage therapy and do not specifically look at factors after ciclosporin or infliximab have been started. Low albumin is predictive of colectomy,220 221 with one study showing that albumin on day 3 of corticosteroid treatment was the only predictor of colectomy on multivariable analysis.222 A CRP/albumin ratio of 0.85 on day 3 of intravenous steroids also predicted colectomy with a sensitivity of 70%, specificity 76%.223 Flexible sigmoidoscopy performed with care is safe in ASUC and gives important information about disease severity.224 Severe endoscopic lesions (deep ulcers, extensive loss of mucosal layers, well-like ulcers or large erosions) have been associated with non-response to corticosteroids225 and colectomy.226 227 A study of 89 ASUC patients treated with intravenous corticosteroids and/or infliximab or ciclosporin used the UCEIS and showed that almost all patients with a UCEIS score of 7 or more on admission required rescue therapy,228 and another study shows UCEIS is predictive of need for rescue therapy and for surgery.229

3.12.3 Ciclosporin or infliximab rescue therapy for ASUC

Patients who do not respond to corticosteroid therapy after 3 days should be considered for second-line ‘rescue’ therapy or surgery. Early clinical risk stratification tools can be used to predict failure of medical therapy (table 5); those at high risk of failure should be offered rescue therapy after discussion with the colorectal surgeon (figure 2).

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Figure 2

Management of acute severe ulcerative colitis.

3.12.4 Ciclosporin in ASUC

The striking benefits of ciclosporin in ASUC were shown in a 1994 paper.230 A randomised controlled trial showed that 2 mg/kg intravenous ciclosporin was as effective as 4 mg/kg in ASUC, with response rates at day 8 of 83% and 82%, respectively with no difference in colectomy rates.231 Reviews have shown short-term colectomy rates in patients receiving intravenous ciclosporin vary from 26% to 47%.196 210 The initial ciclosporin dose is 2 mg/kg/day intravenously with a target trough ciclosporin concentration of 150–250 ng/mL.231 Responders should be converted to an oral dose twice the intravenous dose and administered in divided doses twice daily with a target trough concentration of 100–200 ng/mL.200 Oral ciclosporin should be continued for several months as bridging therapy,230–234 and long-term outcomes are much better if thiopurine maintenance therapy is given, rising from 40% to 66% in one study.235 Those requiring ciclosporin salvage therapy who have already failed thiopurine therapy have much worse outcomes.233 236

Large case series of ciclosporin therapy in UC have reported a significant toxicity profile, with serious infections in 5% of patients and mortality in 1–3%.233 237 238 Major adverse events related to ciclosporin therapy include nephrotoxicity (6.3%), seizures (3.6%), anaphylaxis (0.9%) and death (1.8%).238

3.12.5 Infliximab in ASUC

Infliximab is also effective in ASUC.220 239 240 Long-term follow-up data of the original Swedish trial239 which studied a single infusion of infliximab showed a significantly lower colectomy rate compared with controls (50% vs 76%; p=0.01) at 3 years, without use of maintenance infliximab.241 Contraindications to use include latent tuberculosis (TB), active sepsis, congestive heart failure and demyelination, and screening is required before starting treatment. Combination therapy using azathioprine with infliximab has a synergistic effect, with evidence of benefit in raising infliximab levels and reducing antibody formation against infliximab,242 even in patients who have previously failed monotherapy with thiopurines. Azathioprine or mercaptopurine should be started during hospitalisation and continued after discharge. Once patients have responded well to rescue therapy, corticosteroid doses should be tailed. Prophylaxis for Pneumocystis jirovecii should be given for those on 20 mg prednisolone or more (see Section 5.2.8.6: Common Disease Considerations, Prevention of Pneumocystis jirovecii infection).

3.12.6 Comparison of infliximab and ciclosporin in ASUC

Head-to-head comparisons between ciclosporin and infliximab have demonstrated equivalent efficacy. In the open label CySIF trial, 115 patients previously naïve to infliximab and ciclosporin, who had a Lichtiger score >10 points (range 0–21) and colitis refractory to at least 5 days of intravenous steroids, were randomised in a 1:1 ratio to receive intravenous ciclosporin (2 mg/kg per day for 1 week followed by oral drug until day 98) or infliximab (5 mg/kg on days 0, 14 and 42).243 In both groups, azathioprine was started at day 7 in patients with a clinical response. The primary end-point was treatment failure defined by absence of a clinical response at day 7, a relapse between day 7 and day 98, absence of steroid-free remission at day 98, a severe adverse event leading to treatment interruption, colectomy or death. There was no statistically significant difference between treatment failure in patients given ciclosporin (60%) and infliximab (54%). Nine (16%) patients in the ciclosporin group and 14 (25%) in the infliximab group had severe adverse events, which was also not statistically different. Similar mucosal healing rates (47% ciclosporin, 45% infliximab) and colectomy rates (17% ciclosporin, 21% infliximab) were achieved in both groups. There was no difference in colectomy-free survival at 1 and 5 years in patients treated with either ciclosporin or infliximab.244

The CONSTRUCT trial was an open-label pragmatic randomised trial in 270 patients, who were randomly allocated (1:1) to receive either infliximab (5 mg/kg intravenous infusion given over 2 hours at baseline and again at 2 weeks and 6 weeks after the first infusion) or ciclosporin (2 mg/kg per day by continuous infusion for up to 7 days followed by twice-daily tablets delivering 5.5 mg/kg per day for 12 weeks). The primary outcome was quality-adjusted survival; the area under the curve of scores from the Crohn’s and Ulcerative Colitis Questionnaire completed by participants at baseline, 3 months, and 6 months, then every 6 months from 1 year to 3 years.200 There was no statistically significant difference between the two groups for the primary end-point as well as the secondary end-point of colectomy rates, time to colectomy, serious adverse events or death. Colectomy rates were 29% for infliximab and 30% for ciclosporin at 3 months, and 35% and 45% respectively at 1 year, with no significant difference between the treatments.200 However, treatment with infliximab was associated with greater cost of treatment compared with ciclosporin.

A meta-analysis of infliximab and ciclosporin randomised controlled trials shows no difference in response up to 1 year.245 In the Spanish ENEIDA registry, where patients with steroid unresponsive ASUC were treated with ciclosporin (the majority of whom were given azathioprine maintenance therapy), the colectomy rate at 5 years was 25.4%. For those treated with infliximab, either continuing repeat infusions, combination therapy with azathioprine, or azathioprine only, the 5-year colectomy rate was similar at 26.2%.234

Mortality from infliximab trials is comparable to data on ciclosporin (0–2%).196 210 234 The most significant risk for both infliximab and ciclosporin relates to those on either of these drugs combined with high-dose corticosteroids who fail medical treatment and go on to colectomy with deteriorating physical condition (anaemia, hypoalbuminaemia and oedema) where surgical complications are a significant concern (see Section 3.12.9:Ulcerative Colitis, Surgery for acute severe UC).

Ciclosporin and infliximab are equally effective in ASUC. Infliximab, however, is simpler to use and is thus used much more widely now. Although infliximab was more expensive, use of biosimilars is bringing costs down.

3.12.7 Sequential therapy (infliximab and ciclosporin) in refractory ASUC

Sequential therapy with infliximab and ciclosporin can be associated with profound immunosuppression and potentially risks serious adverse events and infections and is not recommended,246 247 although a recent review suggested that the risks were not excessive (on the basis of low-quality data).248 In the ENEIDA registry sequential therapy was defined as treatment with the second agent (ciclosporin or infliximab) within 3 months after the steroid-refractory ASUC attack, and was used in 10% of those with long-term outcomes available.234 The median time between treatments was 24 days (95% CI 2.5 to 75.0), and showed comparable safety to use of one rescue therapy only. The greatest risk of this approach is delaying surgery in a patient whose physical condition is deteriorating.

3.12.8 Accelerated infliximab induction regimen in ASUC

Recent studies have demonstrated an association between higher serum levels of anti-TNF and better outcomes.249 A post hoc analysis of ACT 1 and 2 clinical trials noted that patients in the lowest quartile of infliximab serum concentration were less likely to achieve clinical response, remission and mucosal healing, independent of randomised dose (5 mg/kg or 10 mg/kg).250

Various factors, including a high TNF burden in ASUC, proteolytic degradation of anti-TNF associated with increased drug clearance and faecal losses from increased gut permeability due to severe inflammation, support the need for dose optimisation of infliximab in the acute phase.251 In a recent study, serum and non-inflamed tissue anti-TNF drug levels were shown to be related, but serum and tissue drug levels were not associated in inflamed tissue.252 This suggests that high mucosal cytokine levels during inflammation act as a ‘sink’ for drug, and thus a higher serum level of the drug may be required to neutralise tissue TNF. In another study, a high baseline CRP (>50 mg/L) and a low serum albumin (<35 g/L), as surrogates for severe inflammation and extensive colitis, independently correlated with lower infliximab concentrations from week 0–6.253

There is further evidence of benefit with accelerated infliximab dosing in ASUC. Three doses of accelerated infliximab dosing at 5 mg/kg, administered over a median 24 days to steroid-refractory patients, demonstrated a colectomy rate of 6.7% compared with 40% in a retrospective cohort (standard 5 mg/kg induction at 0, 2 and 6 weeks).254 For those completing induction therapy, the colectomy rates during follow-up were similar (median follow-up of 2.4 years for standard dosing and 1.6 years for accelerated dosing regimen). A recent review suggested that dose intensification may benefit half of patients with ASUC treated with infliximab, with case control studies showing that 1–2 extra infusions in the first 3 weeks can dramatically reduce colectomy rates.251

Patients treated with infliximab who are not responding sufficiently to a 5 mg/kg dose after 3–5 days can be treated with an early repeat infusion, particularly in those with a low albumin (below 35 g/L). Some clinicians use an initial 10 mg/kg dose as salvage therapy but there is as yet insufficient data to demonstrate the value of this in comparison to a 5 mg/kg dose.255 Optimal timing and dose (5 mg/kg or 10 mg/kg) are as yet unclear. Accelerated dosing should only be given after colorectal surgical review, with agreement that colectomy is not required imminently (see figure 2). Further studies are required to evaluate the use of drug levels and biomarkers to determine personalised dosing for patients.

3.12.9 Colectomy for ASUC

Outcomes from ASUC were revolutionised by the use of corticosteroids and the introduction of timely surgery in those who had not responded. Mortality plummeted from 24% to <1% in the landmark studies.102 256 Despite rescue therapy, a significant number of patients still go to surgery in the acute situation. Although meta-analysis has not shown evidence that infliximab increases postoperative complications in UC,257 a recent series has shown that outcomes for surgery have been worse since the introduction of biologics.258 One possible explanation for this discrepancy would be that, in the case of ASUC, using biologics as rescue therapy after failure of corticosteroids creates a delay in surgery. Although thromboembolic complications are a significant risk,259 a recent study did not show a difference between those going to surgery after steroids only and those receiving steroids and ‘rescue therapy’ prior to colectomy. Both groups however had been inpatients for a long time before surgery (10 vs 12 days).260

Timely decision-making is therefore important in order to prevent delays or prolongation of medical therapy, as those failing medical therapy and undergoing colectomy have higher postoperative complication rates after delayed surgery.105 Prolonged admission prior to surgery was the only significant predictor of postoperative complications in another study.261 In a study from the USA, mortality in those who had colectomy within 3 days of admission was used as a comparator.262 For those with colectomy up to 6 days, the adjusted ORs for postoperative death was 2.12 (95% CI 1.13 to 3.97) and 2.89 (95% CI 1.41 to 5.91) for colectomy up to 11 days.

Multidisciplinary team involvement with gastroenterologist, colorectal surgeon, and stoma therapist enables better management.196 263 Surgical input at an early stage helps patients to understand that colectomy is an important treatment option and is not an outcome to be avoided at any cost. Prompt joint decision-making is essential to avoid unnecessary delays (figure 2).

3.13.1 Emergency colectomy for UC

Surgery in ASUC is indicated when the disease is medically resistant, there are intolerable side effects of medication, or when there is life-threatening haemorrhage, toxic megacolon or perforation.264 Toxic megacolon is a devastating complication of severe colitis, characterised by radiographic distension of the colon often with fever, tachycardia, neutrophil leucocytosis and anaemia.

In this setting, the operation of choice is a subtotal colectomy and end ileostomy with long rectal stump.259 265 266 This could be performed laparoscopically or open according to local expertise, although a laparoscopic approach is likely to result in shorter length of stay and reduced risk of infectious complications.267–269

Care should be taken to avoid leakage from the rectosigmoid stump, either by formation of mucous fistula, locating the top of the remnant in the subcutaneous tissue of the abdominal wall, or closing the stump but leaving a transanal catheter in the initial postoperative period to prevent stump ’blow-out', with no clear evidence of the preferred technique.269 If the patient wishes to consider restoration of intestinal continuity with a proctectomy and ileoanal pouch, this should not be undertaken in the acute setting, given the significant risk of complications in a patient who is likely to be clinically unwell, hypoalbuminaemic and on immunosuppressive medication. Timing of pouch surgery should be an individualised decision with multidisciplinary input, with a minimum of 3 months and preferably 6 months from the initial subtotal colectomy in order that adhesions may be safely manageable and the patient allowed time to generally recover from the initial procedure. A population cohort study from Sweden showed that the median time to subsequent reconstructive surgery is almost 12 months.270 At the time of ileoanal pouch surgery, a temporary covering loop ileostomy will reduce the clinical anastomotic leak rate as well as the septic sequelae of a leak, but may be omitted in optimal circumstances.269 A subsequent anastomotic leak from a non-defunctioned ileal pouch-anal anastomosis would generally require defunctioning.

3.13.2 Outcomes after colectomy for UC

Proctocolectomy followed by ileal pouch anal anastomosis (IPAA) is well-established as a management option for UC. Multiple case series have demonstrated good outcomes in terms of quality of life, with a majority of patients indicating they would undertake the same procedure again.271–274 In one of the larger series, 95% of patients reported good or excellent functional and quality of life outcomes over up to 10 years of follow-up.273 A further study showed no deterioration in functional outcome over 10 years or more.275 Comparison with medical therapies are difficult since there are no published comparative data, and in the absence of randomisation there would be selection bias. Comparison of IPAA to end ileostomy suggests that both are associated with equivalent quality of life, and the decision should be a matter of patient choice after detailed explanation and counselling. Functional outcomes are just as good after laparoscopic-assisted pouch surgery.276

Ileoanal pouch surgery is not currently a centralised service in the UK. However, data from the UK suggest that high-volume centres (more than 100 procedures between 1996 and 2008) had lower pouch failure rates.277 In this study, high-volume centres had a pouch failure rate of 5.2%, similar to the rate of 5.3% reported from the Cleveland Clinic (5.3%) in the USA.273 A further study showed that there is a significant learning curve for pouch surgery, with improving outcomes dependent on the number of procedures undertaken for both trainees and senior staff.278 Likewise, there is evidence that management of leaks after IPAA procedure improves with increasing experience, and results in better pouch salvage rates.279

3.13.3 Surgery in UC patients with primary sclerosing cholangitis

While the occurrence of complications following IPAA surgery in patients with co-existent UC and primary sclerosing cholangitis (PSC) is high, the risk of pouch failure is low. The most common short- and long-term complication is pouchitis, with acute, recurrent acute and chronic pouchitis all occurring frequently. The largest published series of 100 patients with co-existent UC and PSC with IPAA followed for a median of 5.9 years, reports 30-day complication rates of 39% and overall pouchitis rates of 64%.280 Pouch excision was only necessary in 3% of patients in this series. Other smaller series present similar data with high rates of pouchitis, although whether the rate is higher than in the non-PSC UC cohort is unclear, with data conflicting.281–283 For PSC patients with UC undergoing liver transplantation, graft outcomes are better for those who have an end ileostomy after colectomy compared with colectomy and IPAA.284 Graft loss was mainly associated with hepatic artery thrombosis and biliary strictures. The risk associated with IPAA is not dependent on the timing of colectomy in relation to the liver transplantation. Patients can be offered pouch formation if they have PSC as long as they understand the potential implications.

3.13.4 Fertility and delivery after restorative proctocolectomy

Any pelvic surgery incurs a risk to fertility. Whereas there is evidence that medical treatment of UC does not impair female fertility,285 a retrospective systematic review and meta-analysis of fertility rates 1 year after open IPAA surgery showed 63% infertility with a relative risk of 3.91 associated with the surgery,286 corroborating an earlier meta-analysis showing an infertility rate of 15% for medically-treated UC and 48% after IPAA.287 Time to conception is longer post-surgery, with a more frequent necessity of in vitro fertilisation and higher incidence of caesarean section.288 It is likely that Fallopian tube scarring in relation to the procedure is the cause of infertility.286 In selected female patients without proctitis, subtotal colectomy with ileorectal anastomosis (IRA) may be preferable as this does not impair fertility,289 although this procedure is not suitable for all and the long-term risk of rectal malignancy remains following IRA. There is evidence that pelvic scarring is much reduced when IPAA is performed laparoscopically.290 Consistent with this, time to first spontaneous pregnancy following IPAA is shorter in those undergoing laparoscopic surgery in comparison to open procedures.291 In a retrospective questionnaire-based study comparing fertility in 15 women following laparoscopic IPAA to that in a control group having appendectomy, infertility was demonstrated in 27% which was no different to the control group,292 suggesting that laparoscopic restorative proctocolectomy may be the preferred option for female patients of reproductive age.

3.14.1 Assessment of new symptoms after IPAA

Up to 50% of patients will develop pouchitis at some time after IPAA (as many as 40% in the first year). Typical symptoms of pouchitis include increased bowel frequency, urgency, nocturnal seepage or incontinence, pelvic discomfort and abdominal cramps (table 6).293 Diagnosis is based on the presence of symptoms in conjunction with endoscopic appearance and histology to rule out other conditions. Patients who develop symptoms may not have pouchitis: post-surgical complications should be considered particularly within the first year after surgery.294 This can be due to fistula development, pelvic sepsis and anatomical problems related to pouch construction (for instance, long cuffs with flutter valve effects or mechanical causes of poor pouch emptying). A study in 68 patients with antibiotic-dependent or refractory primary idiopathic pouchitis, who had had both pouchoscopy and pelvic MRI, showed that 38% had chronic peri-pouch sepsis. Those with sepsis more often had inflammation in the upper pouch only, and although some had a collection that could be drained radiologically, outcomes were poor with most remaining on long-term antibiotics and nearly a third having a defunctioning stoma or pouch excision.293 In patients with chronic pouchitis 20%–30% have secondary causes for their symptoms, which include CMV infection, Candida, Clostridium difficile, 295 ischaemia, autoimmune disorder, or damage from radiotherapy, chemotherapy or non-steroidal anti-inflammatory drugs.180 296 A proportion may have Crohn’s disease, with reported frequency ranging from 3.6%–13%.297

Endoscopy is the main tool in the diagnosis and differential diagnosis of pouchitis. The most commonly used clinical scores for pouchitis evaluation are the Pouchitis Disease Activity Index (based on symptoms, endoscopy and histology (table 6) and the simpler Modified Pouchitis Disease Activity Index (symptoms and endoscopy only).298 299 In both, endoscopy is key. Pouchoscopy may be best carried out using a gastroscope in view of the flexibility and smaller calibre of this compared with a colonoscope, and a digital examination adds valuable information. At the time of pouchoscopy it is important to assess the pre-pouch ileum as well as the pouch itself, the rectal cuff and anal transition zone (to look for cuffitis). Morphological changes of oedema, loss of vascular pattern, erythema, haemorrhage, erosions/ulceration should be looked for. Ulcers in the afferent loop may indicate Crohn’s disease or use of NSAIDs. Inflammation in one half of the pouch with sharp demarcation along the suture line may suggest ischaemia. Staple-line ulcers with normal pouch mucosa elsewhere are common and do not suggest pouchitis.296 300 Other investigations include pelvic MRI to rule out collections, fistulae or anatomical abnormalities; stool cultures and C. difficile toxin and celiac serology.

3.14.2 Treatment of acute pouchitis

Antibiotic therapy is the standard treatment for acute pouchitis,301 with observational data demonstrating 96% of patients have a symptomatic response to antibiotics.302 There is very little evidence comparing different antibiotics. However, one small study of 16 patients demonstrated that ciprofloxacin was superior to metronidazole in the treatment of acute pouchitis.303 Ciprofloxacin is better tolerated with fewer adverse effects than metronidazole and may therefore be considered first line treatment for acute pouchitis.304

There is one trial of probiotics in primary prevention of pouchitis. Forty patients were randomised to a specific probiotic mixture containing eight bacterial strains, or placebo.305 Ten percent of the probiotic treated arm developed pouchitis in a year compared with 40% of the placebo-treated group. An uncontrolled retrospective study reported primary prophylaxis with sulphasalazine 2 g. At a median 68 months, pouchitis occurred in 15% on sulphasalazine, compared with 64.5% not given the drug.306

There are more studies examining secondary prevention of pouchitis. Two trials show benefit for a probiotic mixture of eight bacterial strains given after a 1 month course of antibiotics for patients with chronic relapsing pouchitis.307 308 An open-label study of a probiotic mixture in 28 patients without symptoms, (36% had previous pouchitis but none had symptoms at study entry) designed to evaluate immunological changes in the pouch, showed progressive improvement in PDAI scores over 1 year, and expansion of mucosal regulatory T cells, compared with patients on no treatment.309 A small study of Lactobacillus rhamnosus GG over 3 months (in patients with previous pouchitis, and with endoscopic pouch inflammation, but no symptoms) showed no benefit.310 Overall trial quality in these studies was low, and further trials would be helpful to clarify management.304 311 Probiotic therapy can be recommended for prevention of relapsing pouchitis, but there is insufficient evidence to recommend primary prophylactic probiotics after pouch surgery, or even whether this should be given to those at higher risk of pouchitis, such as those with pre-operative extra-intestinal manifestations, primary sclerosing cholangitis or high titres of p-ANCA.312 313 Recent studies have shown that alterations in pre-colectomy bacterial microbiota are predictive of subsequent pouchitis, with increases in Ruminococcus gnavus, Bacteroides vulgatus, Clostridium perfringens, and absence of Lachnospiraceae genera (Blautia and Roseburia) and this may inform future treatment strategies.314 A small open-label study of faecal microbial transplantation (FMT), (single treatment via nasogastric tube) in 10 patients with chronic pouchitis did not show obvious clinical benefit.315

FMT can be used to treat Clostridium difficile infection in the context of ulcerative colitis when first line antibiotics are ineffective.316 There is currently no place for FMT in the management of IBD unless complicated by C. difficile infection outside of the clinical trial setting.

Anti-diarrhoeal drugs are often used by patients with IPAA to reduce bowel frequency. There is no evidence of benefit in pouchitis treatment although they are often continued. More evidence is required to support this common practice.

3.14.3 Treatment of chronic pouchitis

Chronic pouchitis or chronic refractory pouchitis is defined as occurring when patients with pouchitis remain symptomatic despite 4 weeks’ treatment with antibiotics. Patients who fail to respond to 2 weeks of an antibiotic, or relapse rapidly after stopping, can be treated with a combination of antibiotics for 4 weeks. Ciprofloxacin plus rifaximin and ciprofloxacin plus tinidazole have been shown to be effective in randomised controlled trials.301 Oral budesonide 9 mg and oral beclomethasone dipropionate 10 mg daily given for 8 weeks have also been shown to be effective,317 318 and if symptoms worsen on stopping, biologics should be considered rather than continuing long-term steroids. Some antibiotic-dependent patients may require long-term rotating antibiotic therapy, and coliform sensitivity testing may help to choose appropriate agents.319 Patients with pre-pouch ileitis (occurring in 6% of patients with pouchitis) represent a high-risk group for chronic refractory pouchitis and should be considered for early escalation to immunomodulatory therapy.320

3.14.4 Treatment with biologics in chronic refractory pouchitis

Patients developing chronic treatment-refractory pouchitis should be re-evaluated to exclude other causes (see above). A recent systematic review with meta-analysis of the literature regarding the use of anti-TNF therapy for patients with chronic refractory pouchitis has shown moderate to good benefit in eight case series for infliximab and adalimumab therapy with a pooled remission rate of 53%.301 A preliminary report of a small double-blind randomised trial of adalimumab for chronic refractory pouchitis showed that six patients on adalimumab all improved, with only two of seven on placebo improving. The study was too small for statistical significance.321 A series of 20 patients with chronic antibiotic-dependent, or refractory pouchitis showed benefit with vedolizumab therapy. Assessed at 14 weeks, PDAI and Oresland scores improved with 17/19 patients able to stop antibiotic therapy.322 A small open-label study of 10 patients using tacrolimus enemas (0.08 mg/kg) showed response in nine, and remission in seven.323

3.14.5 Follow-up of pouch patients

Ulcerative colitis patients who have undergone ileoanal pouch anastomosis represent a small group of patients, who have undergone a specialised procedure with a 5%–10% chance of long-term failure and significant risk of complications,324 of which pouchitis is the most frequent. A pouch clinic enhances patient satisfaction,325 and facilitates data collection for audit and research purposes. Participation in a national pouch registry is invaluable for this purpose.326

3.14.6 Pouch surveillance

The risk of neoplasia in pouches is extremely small, with a risk of cancer less than 0.02% at 20 years.327 328 Cancer may arise following pouch surgery within the rectal cuff, within the pouch itself or arise from the skin (squamous cell carcinoma).329 Risk of pouch-associated neoplasia is elevated in patients with a diagnosis of IBD-associated cancer,330 family history of colorectal cancer, type C ileal changes (severe pouchitis rapidly after pouch formation, with moderate to severe villous atrophy), long retained rectal cuff, and primary sclerosing cholangitis.331 Although controversial, annual pouchoscopy is recommended by most commentators for these high-risk patient groups.332 333 The indications for pouch surveillance in the asymptomatic population without the above risk factors is uncertain,328 although abnormal endoscopic findings are not uncommon.334 335 A decision in this low-risk group to either perform no surveillance unless symptomatic, or 5-yearly, should be discussed with the patient, and documented. Examinations should be performed by an experienced endoscopist.

4.1.1 Phenotypic classification

The Montreal classification29 is widely used to classify the key phenotypic features of patients with Crohn’s disease.22 In order to capture the change in disease location and behaviour over time, and growth failure in the paediatric IBD phenotype, the Paris classification was developed as a modification of Montreal (table 7).23 337 338 Using these classification systems in clinical practice is useful to ensure appropriate decision-making regarding surgery, medical treatment and surveillance. Montreal and Paris define disease extent according to endoscopic or macroscopic features. With an increasing emphasis on mucosal healing as a therapeutic target, it is important to note that histological evidence of inflammation may be more extensive than macroscopic features. This has been shown in paediatric studies, where inclusion of histological inflammation increases those classified with ileal involvement from 49% to 71.3%, those classified with Paris L3 disease increases by 10%, those with Paris L3+L4a by 24% and those with Paris L4 disease by 27%.339–341 A further approach to classifying disease relates to defining early disease: there is evidence that early treatment with biologics is more effective and an international consensus has proposed a Paris Definition for Early Crohn’s Disease, defined as disease duration of 18 months or less after diagnosis without previous exposure to immunomodulators and/or biologics.337

4.1.2 Clinical and endoscopic disease activity

The Crohn’s disease activity index (CDAI)342 has in the past been used in clinical trials,343 but it has a number of limitations, including the parameters used to define remission (CDAI <150), and contemporary trial design no longer favours use of CDAI.344 In clinical practice, CDAI is cumbersome to calculate, requires diary data from patients, is weighted towards diarrhoea (which is often caused by factors other than inflammation), is not usable in patients with stomas and is not validated for use after surgery. In contrast, the Harvey Bradshaw Index (HBI) is both simple to calculate and measure, and less susceptible to confounding factors relying on clinical parameters only, yet is heavily weighted by diarrhoea.345 An HBI score ≤4 is often used to define clinical remission. There is also value in monitoring patient-reported outcome measures (PROMs), reflecting the overall impact of disease on the individual.346 The IBD-Control PROM is an easy to use, reliable 8-item measure which correlates well with other quality of life measures347 and should be used to monitor patients’ perspective of their disease. It should be noted that neither HBI nor PROMs measures correlate well with objective markers of inflammation in Crohn’s disease,348 as subjective factors including psychological status impact significantly on patient-reported well-being. These measures are thus complementary to objective measures of disease activity obtained at endoscopy, imaging and surrogate measures including faecal calprotectin. More objective measures of disease impact including the Lemann index349 and endoscopic inflammation scores are more useful as treatment targets in clinical trials,350 and may drive therapeutic decision-making in clinical practice.

There are a number of endoscopic scoring systems which are used regularly in clinical trials351 352 although the two most commonly used are the Crohn’s Disease Endoscopic Index of Severity (CDEIS)353 and the Simplified Endoscopic activity Score for Crohn’s disease (SES-CD; table 8).354 While the CDEIS is complex to calculate, the SES-CD is a simple, reproducible and reliable endoscopic score.355 356 Both are used to assess for complete mucosal healing as an end-point in clinical trials. Although not used extensively in routine clinical practice, the SES-CD does systematise recording of features in each segment of the colon. Validated MRI activity scores are increasingly used as adjunct end-points in clinical trials.357 358 The Rutgeerts score (table 9) is used specifically to assess recurrent disease in the neo-terminal ileum after surgery.359

In clinical practice there is evidence that treatment escalation and de-escalation driven by objective markers of inflammation that are surrogates for endoscopy (CRP, faecal calprotectin), as well as clinical variables, can result in improved endoscopic and quality of life outcomes, at least in the short term.360 361 (The CALM trial is discussed further in the Section on Use of faecal calprotectin to inform therapy changes 5.5.1.2). It seems likely that this will translate into long-term benefit, but as yet there is no widely agreed treatment target in Crohn’s disease. As safer and more powerful therapies become available, it may be appropriate and feasible to use targets based on these objective measures in routine practice, in addition to clinical symptoms, to ensure effective control of the disease on a long-term basis. The choice of surrogate measure (such as faecal calprotectin), endoscopy, cross-sectional imaging or combinations of these at intervals may differ between patients, depending on their disease distribution, severity and their personal preference.

4.1.3 Diagnostic tests

Ileocolonoscopy with biopsy is established as the first-line investigation for suspected Crohn’s disease. Ileoscopy with biopsy histology is superior in establishing the diagnosis of mild ileal Crohn’s disease, however, intubation of the terminal ileum may not always be possible, and up to 20% of patients have isolated proximal small bowel disease beyond the reach of even complete ileocolonoscopy. For example, out of a cohort of 150 Crohn’s disease patients, 36 had active small bowel disease diagnosed using CT enterography following a normal ileocolonoscopy.362 Ileoscopy and radiological imaging are complementary in diagnosis of ileal Crohn’s disease.363 364 Dedicated small bowel imaging should be performed to complement ileocolonoscopy in all patients with suspected Crohn’s disease and those with an unclassified colitis at ileocolonoscopy. Mucosal biopsy specimens are essential for a complete macroscopic and microscopic assessment of the colon and distal ileum.9 365

Crohn’s disease in the upper gastrointestinal tract has a prevalence up to 13% in some studies,366 and 16% in a more recent study of 119 patients.367 When found, it is usually accompanied by ileal or colonic disease.368 It has been suggested that upper GI endoscopy can help to differentiate between UC and Crohn’s disease in patients with an unclassified colitis. Changes of focal gastritis occur, however, in UC as well as Crohn’s disease,369 and so gastroscopy may not be helpful. If there is vomiting, dyspepsia or other upper GI symptoms then upper GI endoscopy is indicated, but not routinely in adults with suspected or proven Crohn’s disease.

4.2.1 Budesonide in ileocaecal Crohn’s disease

In a randomised double-blind trial, ileal-release budesonide 9 mg once daily for 8 weeks was as effective as prednisolone (40 mg daily tapering to 5 mg at 8 weeks) at inducing remission in patients with mild-to-moderate ileocaecal Crohn’s disease with treatment efficacy (CDAI score <150) of 51% on budesonide at 8 weeks compared with 52.5% for prednisolone,412 and significantly fewer side effects. Multiple meta-analyses have also demonstrated the efficacy of budesonide 9 mg/day over placebo in inducing remission.413–415 A once-daily 9 mg dose is as effective as 3 mg three times daily.416 In the context of more severe disease (CDAI >300) budesonide is inferior to prednisolone (RR 0.52, 95% CI 0.28 to 0.95).414 When remission has been achieved, budesonide should be tapered over 1–2 weeks.

4.2.2 Corticosteroids in colonic Crohn’s disease

In mild, moderate and severe colonic Crohn’s disease, systemic corticosteroids such as prednisolone are effective in inducing remission.417–419 A starting dose of 40 mg tapering by 5 mg weekly is often used, but should be tailored to disease severity and patient tolerance. Ileal-release budesonide does have benefit in Crohn’s disease affecting the proximal colon,412 but there is no evidence of benefit in more distal colonic inflammation. There are no trials of colonic-release budesonide-MMX in Crohn’s disease at present.

4.2.3 Nutritional therapy

4.2.4 Antibiotic therapy

Trials of antibiotic therapy in Crohn’s disease have studied a wide range of antimicrobial agents. While a meta-analysis demonstrated efficacy for these pooled trials over placebo (RR for continued disease activity 0.85 (95% CI 0.73 to 0.99), p=0.03),440 there was such heterogeneity in the agents and dosing regimens used that it makes it difficult to draw meaningful conclusions.

The risk of adverse effects, particularly with prolonged or repeated courses, should also be taken into consideration. In this regard, rifaximin (a non-absorbed oral antibiotic), in an extended-intestinal release formulation has been shown in a large dose-ranging study to be effective, although at a higher dose than usually employed (800 mg BD). However, there was no dose-response, with numerical but not statistical difference to placebo for the 400 mg BD and 1200 mg BD dose.441 442 Rifaximin is unlicensed for this indication.

In a blinded randomised trial in 73 patients with paediatric Crohn’s disease, azithromycin 75 mg/kg 5 days per week for 4 weeks, then metronidazole 20 mg/kg/day for another 4 weeks, compared with metronidazole only for 8 weeks, showed a remission rate of 66% for azithromycin/metronidazole and 39% for metronidazole (p=0.025), although response rates were similar. In 12 patients failing metronidazole, 83% achieved remission on open-label azithromycin.443 There is continuing research interest in antibiotic therapy in Crohn’s disease treatment, but at present antibiotics should only be used in patients with disease complicated by infection (abscesses, bacterial overgrowth, Clostridium difficile) or perianal fistulising disease. Overall the efficacy for antibiotics as induction therapy in mild-moderate Crohn’s disease remains unproven.

The role of Mycobacterium avium subspecies paratuberculosis (MAP) has been debated for many years. A randomised placebo-controlled trial of 2 years therapy with clarithromycin, rifabutin and clofazimine in 213 patients with active Crohn’s disease, with a further year of follow-up, showed early benefit of antibiotics, but overall there was no significant difference in relapse rate during follow-up.444 There was debate about the dosage and formulation chosen, and the study design (with withdrawal of non-responders at week 16). A further phase 3 trial using higher doses was reported in October 2018.445 A total of 331 patients with moderate to severely active Crohn’s disease were randomised to RHB-104 (clarithromycin 95 mg, rifabutin 45 mg and clofazimine 10 mg) five capsules twice daily or placebo for 52 weeks, in addition to their pre-study therapy. At week 26, remission was achieved in 37% versus 23% on placebo (p=0.007), and durable remission (from week 16 to 52) was achieved in 18% versus 9% on placebo (p=0.019). No data are available on endoscopic healing or on persistence of benefit after stopping treatment.

4.2.5 Surgery in localised ileocaecal Crohn’s disease

The LIR!C study compared laparoscopic ileocaecal resection (n=73) to infliximab (n=70) for patients with terminal ileal disease in whom conventional therapy had failed.446 Across a number of comparators there was equivalence between the two approaches, suggesting that resection is a reasonable alternative to medical therapy in this scenario. The LIR!C trial excluded those who had previous resection, a small bowel segment longer than 40 cm, abscesses or where surgery was deemed likely due to pre-stenotic dilatation. During the median follow-up period of 4 years (range 2–6), approximately a third of patients (n=26, 39%) in the infliximab group required surgery while a quarter of patients in the surgery group (n=19, 26%) required infliximab. Taken together, these data suggest resection is a cost-effective intervention based on the cost of originator infliximab.447 Present day medical costs should be lower with the widespread availability of biosimilar infliximab.

4.3.1 Corticosteroids

Systemic corticosteroids are still an effective initial therapy for moderate to severely active Crohn’s disease,418 419 regardless of disease location, but every effort should be made to limit exposure.448 For less severe symptoms in those with ileocaecal disease location, ileal-release budesonide may be tried initially, but if ineffective, prednisolone may be required. For teenagers, particularly where growth has not completed, and for patients with diabetes or steroid intolerance, alternatives can be considered, including EEN.

4.3.2 Early use of biological therapy

In patients with an aggressive disease course or ‘high-risk’ poor prognostic factors, the early introduction of biologics may be considered. High-risk features include: complex (stricturing or penetrating) disease at presentation; perianal fistulising disease; age under 40 years at diagnosis; and need for steroids to control the index flare.449 450 The predictive power of these features is limited. There is great interest in biomarkers that identify a Crohn’s disease subgroup at high risk of an aggressive disease course. A gene expression signature from peripheral CD8 T cells in active untreated IBD has been identified,451 and is now being tested using a whole blood assay in randomised controlled trials of a ‘top-down’ versus accelerated ‘step-up’ therapy.

The decision to start biological therapy should also consider factors such as stage of life, work absence and availability of other treatment options. Discussion in a multidisciplinary team meeting can be helpful. As well as anti-TNF therapy, vedolizumab and ustekinumab can be considered as first-line biologics.

4.4.1 Immunomodulator therapy

Relapse of Crohn’s disease is common on corticosteroid withdrawal, particularly in moderate to severe disease, and early initiation of corticosteroid-sparing therapy is appropriate. Immunomodulators such as azathioprine, mercaptopurine or methotrexate are effective in the maintenance of remission of Crohn’s disease.

4.4.2 Mesalazine

UK data from 1990 to 2010 show over half of patients with Crohn’s disease were prescribed 5-ASA,468 and Swiss data show it is more often given for Crohn’s colitis.469 A Cochrane systematic literature review showed that oral 5-ASA has no efficacy in maintaining clinical remission in Crohn’s disease,470 with similar negative findings in meta-analyses for induction or maintenance.413 414 471 472 A recent review of colonic Crohn’s disease473 showed that there was no benefit for 5-ASA in colonic Crohn’s disease, but two studies have shown possible benefit for sulphasalazine in remission induction.418 419 Thus, 5-ASAs are not recommended for induction or maintenance treatment of Crohn’s disease.

4.4.3 Biological therapy with anti-TNF drugs, vedolizumab or ustekinumab

4.4.4 Haematopoietic stem cell transplantation

Despite the increasing range of drugs available, there are still a number of Crohn’s disease patients with severe resistant disease or in whom surgical resection is not appropriate (usually due to extensive disease or incipient short bowel syndrome). For this group of patients, autologous haematopoietic stem cell transplantation (HSTC) has been used. The ASTIC study, an RCT of autologous HSTC published in 2015, set a high bar for its primary end point (of sustained therapy-free clinical, endoscopic and radiological remission at 1 year) and failed to achieve it.517 One of the 23 patients undergoing HSTC died and serious adverse events (particularly infection) were common, especially in individuals with perianal Crohn’s disease. Nonetheless in this treatment-refractory population there were, among the component parts of the composite primary outcome, suggestions of benefit in some patients and further trial data are needed.518

4.4.5 Leucocyte apheresis

Although a number of uncontrolled studies have suggested possible efficacy of leucocyte apheresis in IBD, a randomised, double-blind controlled trial in 235 patients with moderate to severely active Crohn’s disease showed no benefit of granulocyte/monocyte apheresis over sham apheresis.519

4.6.1 Orofacial granulomatosis

Orofacial granulomatosis (OFG) is a rare disease with similar microscopic appearances to intestinal Crohn’s disease. Granulomatous inflammation is found in about two-thirds of biopsies in OFG but is not needed for a diagnosis.525 The precise relationship between OFG and Crohn’s disease remains uncertain, with oral Crohn’s disease and OFG terminology often overlapping.

Gastroenterologists have been reported to miss around half of oral lesions compatible with oral Crohn’s disease when compared with dentist examination.526

The threshold for luminal assessment should probably be lower in younger patients, where positive findings are more likely. Sarcoidosis, tuberculosis and chronic infection (particularly dental-associated infection) should be considered in the differential diagnosis. Patients should be referred for assessment to an oral medicine clinic.

The current evidence for OFG management relates to case series only. Topical steroids and tacrolimus are often used, but with limited evidence. An 8-week cinnamon and benzoate-free diet was reported in 25 patients with OFG as first-line therapy with 72% responding, but with flares on further consumption of previously eliminated cinnamon/benzoate-containing foods.527 The mechanism of this effect remains unclear and the long-term continuation of such a diet is challenging. Six weeks of exclusive enteral nutrition (EEN) with Elemental 028 has been used successfully to treat 19 of 22 children with OFG, with 10/10 of isolated OFG cases and 10/12 cases with OFG and Crohn’s disease responding.528 Objective criteria for improvement were not reported in this study. Such a diet would naturally eliminate cinnamon and benzoate, so may be overly-exclusive in some patients who might have responded to a more targeted elimination.

In a retrospective cohort of 22 non-Crohn’s disease OFG patients treated with intralesional triamcinolone injection, 63.6% of patients had no disease recurrence after a single course of injections.529 The mean disease-free period after therapy was 28.9 months (95% CI 28.7 to 29.1). Response to azathioprine in OFG was significantly greater in those with Crohn’s-associated disease.530 A small case series of 14 OFG patients, half with Crohn’s disease, treated with infliximab suggested 71% short-term response, but only 33% were still responding at 2 years.531 Two patients with loss of response subsequently responded to adalimumab.

It would seem pragmatic to treat systemic Crohn’s disease with standard therapies in the presence of OFG and to add dietary, topical or intralesional approaches if there is no response. Conversely, systemic treatment of isolated OFG should be conserved for disease unresponsive to more limited approaches.

4.7.1 Medical therapy for strictures

The CREOLE study evaluated 97 Crohn’s disease patients with symptomatic small bowel strictures and assessed response to adalimumab treatment. Treatment was successful at week 24 in 64% of patients, and a prognostic score at baseline was constructed. This included clinical features (use of immunosuppressive drugs at baseline, obstructive symptoms, severity and duration, and MRE features (length of stricture <12 cm, an intermediate proximal small bowel dilatation (18–29 mm), marked enhancement on delayed T1-weighted sequence and absence of fistula). A higher score was associated with greater likelihood of response to therapy. The authors emphasised the complexity of assessing inflammation and stricturing, which nearly always occur together, and the value of both clinical and MRI features in deciding the value of using drug therapy rather than surgery for small bowel strictures.532

Small bowel bacterial overgrowth is common in small bowel Crohn’s disease,533 particularly in areas above strictures, and responds to broad-spectrum antibiotics534 535 (for further detail see the Section on 4.10.1.2.2 Post-surgical management of Crohn’s disease: Small intestinal bacterial overgrowth). For nutritional advice for patients with strictures see box 8.

4.7.2 Surgical therapy for strictures

Rates of surgery for Crohn’s disease appear to be declining.536 537 Patient selection and outcomes in stricturing disease can be optimised by careful assessment of fibrotic burden538 as well as due consideration of alternatives including endoscopic therapy,539–542 and decisions are best taken with joint input from all MDT members. As discussed above, a prognostic score based on MRE features and clinical factors can help in predicting the likely response to anti-TNF therapy. A moderate degree of dilatation proximal to the stricture is associated with greater likelihood of response than either massive dilatation or, rather surprisingly, no dilatation. Having more marked obstructive symptoms, but with a shorter duration, is also associated with success of anti-TNF therapy.532

4.7.3 Strictureplasty

Strictureplasty, a technique for surgical treatment of small bowel strictures without loss of bowel length, is indicated with single or multiple strictures, impending short gut or previous extensive small bowel resection. The presence of fistulae, fistula-associated abscesses or possible carcinoma are contraindications. The presence of active inflammation at the stricture site does not prevent successful strictureplasty.543 Strictureplasty is not associated with increased recurrence or re-operation rates.544–546 In fact, there is evidence re-operation rates may be lower at strictureplasty than resection sites,547 although a meta-analysis of seven studies (688 patients) from 2006 showed a non-significant trend to lower risk of complications if strictureplasty alone was performed, but a non-significant trend to increased recurrence after strictureplasty and significantly longer recurrence-free survival for those having a bowel resection.548 The conventional Heineke–Mikulicz strictureplasty is generally used for strictures up to 10 cm length, with intermediate length (10–25 cm) using a modified technique such as the Finney procedure and an enteroenterostomy (Michelassi procedure) for longer strictures.538 549 The newer techniques are generally as safe and effective as the conventional strictureplasty.550

If multiple small bowel strictures can be dealt with by a single resection in a patient with adequate bowel length elsewhere, then this is preferable to avoid a complex multiple strictureplasty procedure, but such decisions have to be individualised, considering the patient’s condition at the time of surgery (corticosteroid and immunosuppressive drug use, serum albumin, anaemia, nutritional status), potential for postoperative complications from complex surgery and the risk of future malabsorption and malnutrition due to short gut.538 550 551

4.7.4 Endoscopic therapy for strictures

Endoscopic balloon dilatation may prevent or delay the need for surgical resection or strictureplasty for Crohn’s disease-related intestinal strictures, including anastomotic strictures. A key concern is the long-term outcome, in particular the need for surgical resection. A systematic review identifying 24 published studies reported outcomes from 1163 patients, with overall surgical intervention rates over a median follow-up period of 15–70 months of 27%.541 Surgical intervention rates were higher after dilatation of primary strictures, but this did not reach statistical significance. Stricture length <4 cm was associated with a significant reduction in the need for surgical intervention. However, in a different systematic review of largely the same primary papers, 25 studies with data on 1089 undergoing a total of 2664 dilatations estimated the cumulative rate for surgery after 5 years of follow-up as 75%, leading the authors to suggest caution around use of the technique.542 However, this figure may overestimate the ultimate requirement of surgery as 5-year follow-up data were only available in 455 patients, who may have remained in follow-up due to a more complicated disease course. The authors did not find any association between stricture subtype and outcomes.

A small study has shown benefit of intralesional injection of corticosteroids at the time of balloon dilatation of Crohn’s disease strictures,552 but further studies have not shown benefit.553 554

4.8.1 Intra-abdominal abscesses

4.8.2 Medical therapy

In the first instance, patient optimisation is required when localised perforation in Crohn’s disease has led to abscess formation. Surgical intervention is mandatory within the context of free peritonitis and highly likely to be required at some stage in the setting of localised abscess formation. Ideally, surgery takes place following treatment of sepsis and treatment of nutritional deficiencies. Exclusive enteral nutrition can be an effective means of controlling intestinal inflammation without use of corticosteroids.

Some observers suggest that surgery may be avoided by percutaneous radiological drainage of abscesses and then resumption of medical therapy.555 The largest case series to date of 51 patients identified retrospectively from review of medical charts from a single centre over a 10-year period has shown that patients undergoing surgical resection were significantly less likely to develop abscess recurrence than those treated with antibiotics alone or percutaneous drainage over a mean follow-up of 3.75 years (12% vs 56%).556 Nevertheless, non-surgical approaches were successful in preventing subsequent surgery in almost half of the patients treated medically. An almost identical proportion of patients avoided surgery over long-term follow-up in a different series of 32 patients managed with percutaneous drainage for perforating Crohn’s disease.557 This strategy, if successful in treating sepsis, is likely to lead to lower morbidity and potentially lower stoma rates.

4.8.3 Enterovaginal and enterovesical fistulae

Data on the management of non-perianal fistulae, especially from randomised trials, are limited. There are even more limited data on the outcomes of patients treated for specifically entero-gynaecological or enterovesical fistula. Although these fistulae are rare, they are a serious problem to patients with Crohn’s disease. A systematic literature review showed that response to medical therapy (fistula closure) was complete in 38.3% of rectovaginal fistulae and 65.9% of enterovesical fistulae.558 For enterovesical fistulae, risk factors for the need for surgical intervention include sigmoid origin and other complications of Crohn’s disease including small bowel obstruction, abscess formation, other fistulation, ureteric obstruction or urinary tract infection.559 These authors suggest that enterovesical fistulae should be treated medically initially, with surgery reserved for those with bowel obstruction or abscess formation, non-responders or recurrence after medical therapy. In a series of 47 patients with genital fistulae, antibiotics had no lasting benefit, thiopurines resulted in 13% complete and 24% partial response, and anti TNF-alpha therapy gave 17% complete and 30% partial response. Surgery was undertaken in a third of patients, but only 22% had complete response after a first operation and 39% after reintervention. Overall, fistula closure was only achieved in a third of patients.560

These studies highlight that there is still very limited evidence on which to base specific management guidance, but medical therapy alone or in combination with surgery would appear to offer benefit to some patients in the management of enterovaginal and enterovesical fistulae. Patients should be discussed in multidisciplinary meetings and treatment individualised, considering patients’ symptoms and situation.

4.8.4 Enteroenteric fistulae

Enteroenteric fistulae are often asymptomatic and expert consensus guidelines have recognised that these do not always require surgery.561

4.8.5 Enterocutaneous fistulae

Enterocutaneous fistulae usually communicate with segments of active Crohn’s inflammation, often in the context of other complications including intra-abdominal abscess and luminal strictures, or with surgical anastomoses (as a manifestation of the poor healing which characterises Crohn’s disease). Historically, enterocutaneous fistulae were treated surgically but, with the advent of anti-TNF therapy, conservative approaches can be deployed and may lead to definitive fistula closure in some patients. There are no prospective trial data to guide therapy. Both the fistulae and any associated complications will need to be managed together. For example, in the context of a high output fistula with nutritional deficiency and luminal stricture, a patient will require a period of nutritional and biochemical optimisation, control of sepsis and drainage of collections before definitive surgical management.562 563

There is little formal evidence on the role of immunosuppressive therapy. If a fistula is associated with active inflammation then medical therapy is worthwhile, but it is unlikely to help a postoperative fistula.564 A retrospective series of 48 patients with enterocutaneous fistula from GETAID included 21 postoperative fistulae (within 30 days of surgery, most but not all of which were intestinal resections).565 One third had multiple tracts and one quarter had high output. In addition to managing the associated complications, patients were treated with anti-TNF therapy. One third had fistula healing, half of whom relapsed over a median follow-up of 3 years. One third of patients developed an intra-abdominal abscess while on anti-TNF therapy. Surgery was required in 54% of patients overall. Complexity (multiple tracts) and associated stenosis were associated with reduced rates of healing with anti-TNF therapy and increased need for surgery. Increasing complexity of the fistula is associated with adverse outcomes including mortality.566 All patients with enterocutaneous fistulae should be managed by a multidisciplinary team.

4.8.6 Anti-TNF therapy for non-perianal fistulae

Higher quality evidence is available for infliximab relative to adalimumab for the use of anti-TNF therapy in the setting of non-perianal fistulising Crohn’s disease. The ACCENT II trial included 25 women with a total of 27 draining rectovaginal fistulae at baseline.567 Closure at week 14 after open label infliximab induction therapy was achieved for 45% of fistulae. Randomisation to infliximab during maintenance therapy was associated with a longer duration of fistula closure compared with placebo therapy (median 46 weeks vs 33 weeks). Outcomes for patients in ACCENT II with enterocutaneous fistulae have not been reported separately, but these patients represented less than 10% of the total cohort. Adalimumab has never been subjected to a randomised control trial of efficacy in fistulising Crohn’s disease.

4.9.1 Assessment of perianal disease

Multidisciplinary team working in perianal Crohn’s disease is widely regarded as best practice according to expert consensus.561

Pelvic MRI has a well-recognised role in defining the anatomy of perianal fistulae as an adjunct to examination under anaesthesia (EUA). Initial reports of sensitivity compared with EUA suggested rates of 85–89%.568–570 MRI may also pick up a significant burden of non-fistulising perianal disease that would otherwise be missed clinically.570 571 Endoanal ultrasound has also shown high sensitivity, although use is limited in patients with anal or other luminal stenoses.569 570 Interpretation of fistula imaging (MRI or endoanal ultrasound) is dependent on operator expertise.

An experienced colorectal surgeon should perform EUA to assess perianal disease and identify the anatomy of the fistula tracts, as specialist expertise and knowledge are likely to improve identification of all tracts.569 572 573 In a comparison with endoscopic ultrasound and MRI, an experienced operator correctly classified 91% of patients’ perianal fistulae at EUA (95% CI 75% to 98%).569 However, a combination of two tests from MRI, endoanal ultrasound and EUA is recommended to give the optimal assessment.574 Specifically, unless directed by the results of MRI or endoanal ultrasound, then small abscesses or collections may be missed, particularly if there is significant induration or a supralevator collection.574 EUA is more sensitive than MRI in assessment of anal ulceration or anal canal stenosis.571

Assessment of rectal mucosa at the time of EUA is important.572 575 Largely observational data, but with a large effect size, from the pre-biologics era show that outcomes are worse for perianal fistulising disease associated with rectal inflammation. A study from St Mark’s of perianal fistulising Crohn’s disease patients diagnosed in 1993–4 showed that 29% of those with rectal involvement had proctectomy compared with 4% of those with no rectal involvement.576

4.9.2 Seton insertion

EUA permits drainage of abscesses and placement of setons, with evidence that placing setons prior to starting anti-TNF therapy improves rates of healing and reduces recurrence rates.577–579 A recent meta-analysis confirmed the benefits of combined surgical and medical therapy in improving healing and makes recurrent abscess less likely.580 The exception to routine insertion of setons would be patients with rectovaginal fistulae in the absence of an abscess or collection. In this situation, setons may make faecal discharge per vagina worse.

Evidence for the timing of seton removal is unclear. Early studies removed setons at or shortly after the second infliximab infusion.567 577 579 More recent studies suggest later removal, either after completing infliximab induction therapy581 or after at least five infusions.582 Setons need to be removed to permit complete healing of fistula tracks, but if active inflammation is ongoing, then seton removal may result in recurrent abscess. The optimal timing and assessment method remain unclear, and some patients may require long-term setons to avoid or delay proctectomy. Further trials are needed to better understand the optimal management of perianal fistulae in Crohn’s disease.583 584

4.9.3 Anti-TNF therapy post-surgery for complex perianal fistulae

4.9.4 Combined surgical treatment with anti-TNF therapy

None of these studies included initial surgical interventions for the management of fistula tracts. No randomised controlled trial has compared these treatments directly or attempted to evaluate the additional benefit of combination therapy compared with treatment with either surgery or anti-TNF alone. Nevertheless, comparison between these approaches has been the subject of several retrospective studies which have recently been systematically reviewed. Although significant heterogeneity between individual studies limits interpretation, there is a consistent trend towards improved outcomes with combined surgical and anti-TNF treatment.580 583 Careful preparation of the fistula track with curettage to destroy all epithelial tissue and ligation of the internal opening as standard treatment in both active and control arms of one trial of mesenchymal stem cells achieved a ‘placebo’ (surgical preparation only with no active medical treatment) success rate of 34% at week 24.589 It is highly likely that multiple treatment modalities will be needed to control perianal fistulae in Crohn’s disease.590

4.9.5 Vedolizumab and ustekinumab therapy

Post hoc analysis of 57 patients with fistulae (site not specified) in the GEMINI 2 study showed higher rates of closure of draining fistulae at 1 year: 41.2% on 8- weekly vedolizumab (p=0.03 vs placebo) and 22.7% on 4- weekly vedolizumab (not significant vs placebo).497

Data for outcomes for those patients with fistulae at baseline in the CERTIFI phase 2o and UNITI phase 3 studies of ustekinumab have been reported in abstract form, showing a non-significant trend towards improved fistula healing in patients randomised to ustekinumab compared with placebo.591 Additional data suggesting healing with ustekinumab come from relatively small case series of TNF refractory patients.507 508 592 Further controlled trial data are needed to confirm the role of ustekinumab in perianal fistula healing.

4.9.6 Surgical treatment of fistulae

In a survey of British surgeons, commonly performed definitive procedures in the context of perianal Crohn’s disease were removal of draining seton only (70.7%), fistulotomy (57.1%), and less commonly advancement flap (38.9%), fistula plug (36.4%) and the ligation of intersphincteric track (LIFT) procedure (31.8%).593 The reported efficacy of curative surgical options within the context of perianal Crohn’s disease is variable. Advancement flaps and the LIFT technique are effective in selective patients with perianal Crohn’s disease, with healing observed in two-thirds of patients at 1 year in a small prospective study.594 There is, however, progressive failure over time, related to both treatment failure and recurrent disease.595 Video-assisted anal fistula treatment (VAAFT) combined with advancement flap has been reported in complex fistulising Crohn’s disease with an 82% success rate at 9 months.596 Systematic review has demonstrated fistula plugs may be effective in 55% of Crohn’s disease-related fistulae,597 although variation in reported success is wide. A prospective randomised control trial of fibrin glue in 36 patients with Crohn’s disease perianal fistulae showed effective therapy in 38% after 8 weeks.598 In comparison, just 16% of those under observation only after removal of seton achieved remission (p=0.04). The benefit was greater in patients with simple fistulae. Administration of expanded adipose-derived stem cells in addition to fibrin glue appears more effective than fibrin glue alone.599 The long-term efficacy of fibrin glue, collagen plugs and paste is not clear.

4.9.7 Allogeneic adipose-derived stem cell therapy for perianal fistulae

Expanded allogeneic adipose-derived stem cells are simple to administer and safe.600 In a recent phase III study, 212 patients with treatment-refractory complex perianal fistulising Crohn’s disease were randomly assigned to a single intralesional injection of 120 million Cx601 cells (darvadstrocel) or placebo.589 Both active and control groups had an initial EUA with curettage of fistula tracts, and insertion of setons if needed, followed at least 2 weeks later by a further EUA with ligation of the internal fistula opening and injection of the trial treatment into the tissue adjacent to all fistula tracts. Week 24 complete remission rate was 50% for active treatment versus 34% for placebo (p=0.024). The high placebo response rate likely reflects the extensive surgical interventions received by the placebo group including curettage of the fistula tract and closure of the internal opening. Of note, failure of anti-TNF therapy was not a requirement for study entry, but rather patients had to have failed at least one of antibiotics, immunomodulator therapy or anti-TNF therapy. In fact, 79% of patients in this trial had been on an anti-TNF in the previous 6 months and 61% were on anti-TNF therapy at the point of randomisation. One-year outcome data demonstrate combined remission (closure of all treated external openings that were draining at baseline, and absence of collections >2 cm on MRI) of 56.3% in the darvadstrocel group, versus 35.6% in the placebo group (p=0.021). Clinical remission at 1 year was 59.2% and 41.6% respectively (p=0.013).601 Other groups have reported promising data with alternative preparations of allogenic stem cells, reviewed recently.602 Given the complexity of appropriate patient selection, management of luminal disease, surgical technique, selection of adjunct therapies and choice of stem cell preparation, patients offered these therapies should be closely monitored as part of a clinical trial or registry.

4.9.8 Defunctioning stoma formation

Creation of a defunctioning stoma has long been recognised to offer rapid improvement of perianal Crohn’s disease, even in complex cases. The mechanism likely relates to diversion of the faecal stream, which of itself seems to contain factors that promote rectal inflammation.603 Evidence is limited to expert opinion, supported by several case series.604–607 Although many of these series originate from a pre-biologics era, more recent data suggest that rates of successful stoma reversal after ileostomy for complex perianal Crohn’s disease are low.608 609 A systematic review showed that faecal diversion improves symptoms in approximately two-thirds of patients, but bowel restoration is only successful in 17%.610 Rates of successful reversal may be particularly low in those with rectal involvement.610 It should be noted that, after initial improvement, recurrence of inflammation can occur in the pelvis and defunctioned segment of bowel, and may present non-specifically with weight loss, raised inflammatory markers and fevers. For severe refractory disease, proctectomy is an effective treatment, but considered by expert consensus to be a last resort.607

4.10.1 Disease recurrence following ileocolonic resection

In a study of factors predictive of recurrent disease after ileocaecal resection there was a symptomatic recurrence rate of 20% at 1 year and 47% at 5 years. There was a rapid development of endoscopic lesions in the neoterminal ileum (73% at 1 year).359 Risk factors for disease recurrence are discussed in the section below on medical prophylaxis (see Section 4.10.3: Reassessment and medical prophylaxis following ileocolonic resection).

4.10.2 Smoking cessation following surgery

The best described environmental factor affecting the outcome of IBD is cigarette smoking, which has a negative impact on the clinical course of Crohn’s disease. It has been shown that cigarette smokers have quicker and more severe postoperative relapse in Crohn’s disease.621 637 Thus, all efforts should be made to help patients quit smoking after surgery by offering counselling, pharmacotherapy or nicotine replacement therapy (see Section 5.8.1: Smoking and Crohn’s disease).

4.10.3 Reassessment and medical prophylaxis following ileocolonic resection

A summary flowchart of postoperative medical prophylaxis following ileocolonic resection for Crohn’s disease is shown in figure 3.

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Figure 3

Medical prophylaxis after ileocolonic resection for Crohn’s disease.

5.1.1 Tuberculosis

Differentiating between intestinal tuberculosis (TB) and Crohn’s disease may be challenging in those who have lived in endemic areas as clinical features may be similar. Features suggestive of a diagnosis of intestinal TB include night sweats, concomitant pulmonary tuberculosis, positive tuberculin skin test, antibodies to TB, abdominal lymphadenopathy, ascites, transverse ulcers and a patulous ileocecal valve.664–666 Haematochesia, involvement of the sigmoid colon, skip lesions and aphthous ulceration are more common in Crohn’s disease, whereas weight loss may be predictive of TB.665 Extraintestinal manifestations are more commonly associated with Crohn’s disease.666 A recent study from South Korea used 40 Crohn’s patients and 40 with intestinal TB to develop a predictive model using colonoscopic, laboratory and radiological criteria. Features suggesting Crohn’s at colonoscopy were anorectal lesions, longitudinal ulcers, aphthous ulcers and cobblestoning. Colonoscopic features suggesting TB were fewer than four segments of colon involved, patulous ileocaecal valve, transverse ulcers and scars or post-inflammatory polyps. Positive ASCA serology and proximal small bowel disease suggested Crohn’s, and a positive quantiferon gold test and typical pulmonary lesions suggested TB. A score derived from these features was able to make an accurate diagnosis in 96.3% of patients.667 TB PCR performed on intestinal biopsies may be helpful for discrimination between the diseases.668

5.1.2 Enteric infections associated with IBD

The risk of enteric infections is higher in IBD than controls.669 A UK study showed that 10.5% of IBD relapses were associated with enteric infection (half were Clostridium difficile).670 A more recent retrospective study in over 9000 Mayo Clinic IBD patients from whom stools were collected showed a low rate of bacterial infection of less than 3% by culture and PCR (excluding C. difficile infections), with no adverse impact on disease course (higher proportions of stool positive patients remained in remission over the next year compared with those with a non-infective disease flare or C. difficile infection).671 A recent USA study using a multiplex PCR for gastrointestinal pathogens reported that 18.1% and 16.1% of samples from Crohn’s disease and UC patients respectively were positive. Crohn’s disease patients were more likely to have norovirus and Campylobacter, while UC patients were more likely to have bacterial infections, particularly Campylobacter, Plesiomonas and Escherichia coli (compared with non-IBD samples).672 The sensitivity of the molecular test used, the breadth of pick-up of the panel covered and the likelihood of false-positive infections because of asymptomatic carriage all warrant consideration when assessing the literature in this area. Nevertheless, a comprehensive infection screen considering clues from the history, and local infectious epidemiology, is an essential component of evaluating IBD disease flares.

5.1.3 Clostridium difficile infection associated with IBD

Clostridium difficile infection is more common in IBD than non-IBD populations, and in contrast to non-IBD populations, is less associated with PPI and antibiotic therapy.673 674  C. difficile can also be a cause of chronic pouchitis.675

A Canadian population-based case-controlled study of 278 UC patients hospitalised due to a flare of colitis and tested for C. difficile infection identified 6.1% were positive. These patients had an increased risk of colectomy (adjusted OR 3.39) and preoperative C. difficile infection was associated with a higher risk of postoperative infectious complications (OR 4.76).218 Observational studies have shown approximately 20% of IBD patients with C. difficile infection require colectomy.214 676 Outcomes in hospitalised IBD patients with C. difficile infection are worse with higher colectomy rates and higher mortality.215–218 677 678 A systematic review and meta-analysis showed that the 3-month colectomy risk was not increased by C. difficile infection (OR 1.35; 95% CI 0.68 to 2.67) either in IBD or non-IBD populations, but the colectomy risk after 1 year or more was higher for IBD overall (OR 2.23; 95% CI 1.18 to 4.21) and UC specifically (OR 2.96; 95% CI 1.19 to 7.34).679

In non-IBD populations vancomycin is equally as effective as metronidazole for mild C. difficile, but has superior efficacy in severe disease.680 As such, Public Health England recommend vancomycin therapy in severe infection, as do others.219 681 It is not necessary to withhold corticosteroid treatment for acute severe colitis in this situation, and a decision regarding continuation of immunomodulator therapy should be taken on an individual basis (including the surgical team in the discussion).196 681 It is prudent not to escalate therapy or introduce rescue therapy with infliximab or calcineurin inhibitors in ASUC associated with C. difficile infection, as there is little or no data on safety in this situation.

5.1.4 Cytomegalovirus infection in IBD

Cytomegalovirus (CMV) in IBD can be diagnosed by the presence of typical CMV inclusions on H&E stain, immunohistochemistry and/or tissue PCR. A recent systematic review suggested that blood-based testing and histology lack sensitivity to predict reactivation of CMV in the colon and so immunohistochemistry or tissue PCR remain essential in the detection of CMV IBD.682 In a retrospective case control study from the Mayo Clinic, the risk of CMV disease was independently associated with refractory disease, treatment with immunomodulators and age over 30 years.683 Other studies show an association of CMV with corticosteroid use, corticosteroid-refractory UC and leukopaenia.684–687 CMV viraemia and blood PCR have poor sensitivity for diagnosis of CMV colitis, though specificity is high.688 Immunohistochemistry or quantitative PCR can be used to detect CMV on mucosal tissue, and may allow detection of CMV in patients who do not have inclusion bodies on H&E staining.689–692 A recent systematic review has identified wide heterogeneity of the definitions of CMV infection and CMV intestinal disease.693 Due to this heterogeneity, the prevalence of CMV intestinal disease in IBD varies from 2% to 38%. Tissue PCR has a sensitivity of 65% to 100% and a specificity of 40% to 100% whilst immunohistochemistry had a sensitivity of 93% and a specificity of 92% to 100%. These are the preferred methods of diagnosis.

5.2.1 Prevention of infection related to IBD and immunosuppressive therapy

If evidence of active HBV, latent or active TB, HCV or HIV infection, seek specialist input prior to commencing immune modifying therapy.

All IBD patients should be screened at diagnosis for infection risk, as there is both an increased risk of infection as a result of the disease and a high likelihood of requiring immunosuppressive drug therapy (box 4). Patients without a clear history of chickenpox, shingles or receipt of two doses of varicella vaccine should be tested for varicella zoster virus (VZV) IgG. All patients with IBD should be screened for hepatitis B and C, and HIV. The prevalence of hepatitis B and C viral infection in IBD was similar to the general population in 315 patients from France (hepatitis B virus 2.54%, hepatitis C virus 0.95%).703 A Dutch study showed that rates of screening for hepatitis B remain suboptimal at 36–49%.704 Opportunistic testing for HIV should be done at the same time, as the condition is treatable and has public health implications. A panel of viral screening at diagnosis makes it more likely that patients can receive appropriate vaccinations with less delay to receiving immunomodulator therapy, which is now used in at least half of patients at some stage in their disease course. For the same reason, checking thiopurine methyltransferase (TPMT) status early reduces delays in starting thiopurines.

5.2.2 Drug management: thiopurines

A checklist of considerations when commencing thiopurines is shown in box 6, and table 10 gives a guide on interpretation of thiopurine metabolites during dose optimisation. Practical management of thiopurine side effects is described in box 7.

5.2.3 Drug use: methotrexate

Gastrointestinal and liver toxicity of methotrexate is reduced by administration of folic acid, either 1 mg daily or 5 mg weekly, traditionally taken 1 or 2 days after the methotrexate dose.779 780 Methotrexate has comparable safety to thiopurines.781 782 Risk of cirrhosis is much lower than previously thought and routine liver biopsy after prolonged use is not necessary. Abnormalities of liver function can be transitory; in one study of 87 IBD patients (with a cumulative methotrexate dose of 1813 mg) this occurred in 24% of patients treated, but many normalised without stopping methotrexate and only 5% had to stop the drug.783 In this study 17 liver biopsies were performed, none showing advanced liver fibrosis or cirrhosis. Another study of 518 patients on methotrexate for inflammatory disease (24% with Crohn’s) assessed liver fibrosis by transient elastography.784 Six percent (31 patients) had FibroScan results suggesting severe liver fibrosis (4% of the Crohn’s disease patients). Only 13 went on to liver biopsy, with just under half having severe fibrosis confirmed histologically. On multivariable analysis, BMI >28 kg/m² and alcohol intake >14 drinks per week were independent predictors of FibroScan values >7.9 kPa. Patients with these additional risk factors should be screened using transient elastography. For all patients, methotrexate should be stopped if transaminases exceed twice the upper limit of normal. Pulmonary toxicity in the form of acute interstitial pneumonitis presents with dyspnoea, dry cough and fever, and is rare. Most cases are reversible on withdrawal of methotrexate.781 All patients commencing methotrexate should have a baseline chest x-ray.

5.2.4 Drug management: anti-TNF including biosimilars